Download 1 Professor D.Sci. Judit Kosáry Nutritional biochemistry of the

Professor D.Sci. Judit Kosáry
Nutritional biochemistry of the vitamins and secondary metabolites (2016-2)
(Lectures for students with advanced knowledge of biochemistry and food chemistry)
The lectures present the known biochemical functions of the vitamins and the possible
explanations for the effects of their deficiency or excess. The biosynthesis of vitamins and
secondary metabolites used in food industry is also discussed. All of vitamins and other agents
are detailed in point of their:
 biosynthesis,
 metabolism,
 metabolic functions,
 deficiency and excess,
 nutritional status,
 uses in food industry,
 pharmacological uses.
Topics:
1. Definition and nomenclature of vitamins, their nutritional status and non-nutritional uses.
2. Precursors of reagents for biochemical reactions (molecules with coenzyme function) (watersoluble vitamins):
a) Precursors of coenzymes of oxydoreductases : niacin, riboflavin, ascorbic acid.
b) Precursors of coenzymes of transferases:
1. C1 transfer: biotin, folic acid, cyanocobalamin,
2. C2 transfer: thiamin, pantothenic acid,
3. transfer of other groups: pyridoxine.
c) Compounds of doubtful vitamin status: taurine, carnitine, choline, inositol.
3. Vitamins of other functions – vitamin lipids (fat-soluble vitamins):
1. retinol and -carotene,
2. cholecalciferol and its vitamers,
3. tocopherols,
4. phylloquinone and its vitamers,
4. Definition and types of secondary metabolites. Secondary metabolites used in food industry
(e.g. flavour agents of spices, pigments, antioxidants, etc.).
The lectures also present information about the biochemical functions and the metabolism
of some important types of secondary metabolites, which are of different molecules of the living
organisms, and they are more or less needed for their functioning. Secondary metabolites are
synthesized from the different intermediates of biomolecules. The presented types of secondary
metabolites are coenzymes, regulating (e.g. hormones), attracting (e.g. the sweet sucrose, the fruit
esters as scent agents etc.) and repelling agents (e.g. alkaloids and toxins).
Literature: Bender, D.A.: Nutritional biochemistry of vitamins. Cambridge University
Press Cambridge New York Port Chester Melbourne Sydney 1992; Luckner, M.: Secondary
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metabolism in microorganisms, plants and animals Springer Verlag Berlin Heidelberg New York
London Paris Tokyo Hong Kong 1990.
Nutritional biochemistry of the vitamins and secondary metabolites
Professor D.Sci. Judit Kosáry
The vitamins are a disparate group of organic compounds whose only common feature is
that they are essential (cannot be synthesized inside) and required in small amount for the normal
functioning of higher animals and the human body, therefore they must be provided in nutrition.
These compounds can be synthesized by plants and – some of them – by animals from
intermediates of their primary metabolic pathways. According to their role vitamins have diverse
functions in the human metabolism. Polar (“water-soluble”) vitamins are precursors of reagents
so-called coenzymes in metabolic organic chemical reactions. The water-soluble vitamins are
vitamin C and a series known as the vitamin B complex. Nonpolar (apolar) (“lipid-soluble or fatsoluble”) vitamins can be hormones, modulators or regulators and non-specific antioxidants in
human metabolism.
In contrast with primary metabolism that is practically identical in all types of living
organisms, secondary metabolism is a collection of a wide variety of biochemical pathways
characteristic for only a few species of organisms and their distribution is different in specialized
cells. Compounds formed in these reactions called secondary products. According to their
biosynthetic pathways vitamins can be considered secondary metabolits but with a view to their
formation in cell-division (cytogenesis) vitamins can be classified as primary metabolits.
In the course Nutritional biochemistry of the vitamins and secondary metabolites the
vitamins are discussed in topics: biosynthesis; metabolism; metabolic functions; explain the
effects of deficiency and excess; nutritional status; uses in food industry; pharmacological uses
and scientific basis for Recommended Intakes. Topics for secondary metabolites used in food
industry: flavour agents, pigments, antioxidants, etc.
1. Definition and nomenclature of vitamins. Their nutritional status and non-nutritional uses.
Essential compounds
A compound, that the human body cannot synthesize them from other compounds at the
level needed for normal growth, is called an essential compound. These materials must be
obtained from food. The essential amino acids (Val, Leu, Ile, Phe, Lys, Thr, Trp, Met, Arg, His)
are needed in a large quantity. Of other essential compounds we only need small quantities e.g.
vitamins).
Definition of vitamins
The vitamins are a disparate group of organic compounds whose only common feature is
that they are essential (cannot be synthesized inside) and required in small amount for the normal
functioning of higher animals and the human body, therefore they must be provided in nutrition.
These molecules serve nearly the same roles in all forms of life, but higher animals (and human
body) have lost the ability to synthesize them. The original definition of vitamins based on their
dietary essential, but now it is partly a historical category. Later it was proved that some of
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vitamins could be synthesized in the body (e.g. tocopherol and niacin). Nevertheless, for
historical reasons these compounds are classified as vitamins.
At the beginning of the twentieth century the history of vitamins started by feeding
experiments of Hopkins, who found that animals fed by known and characterised nutrients as fats,
proteins, carbohydrates and mineral salt failed to grow without addition a small amount of milk.
Hopkins suggested that milk contained ‘accessory growth factors’. The characteristic functional
group of the first of ‘accesory food factors” isolated was an amine (thiamin). Therefore these kind
of food factors were called by Funk (1912) ‘vitamin’ from the combination of the Latin
expression of the word ‘life’ (vita) and the name of the functional group (amine). Later it came to
light that the presence of an amine group is not essential forl of vitamins, besides the structures
and functional groups of vitamins are highly various but the name ‘vitamin’ is preserved.
Nomenclature of vitamins
At first vitamins had an apparently illoginal system of accepted trivial nomenclature then
after identification they got chemical names and short ‘accepted’ names, as well. The basis of the
trivial system was on one hand the polar-apolar properties of the vitamin (water-soluble and fatsoluble) and the other hand the order (sequence) of isolation according to ABC. For example at
first the name of all of water-soluble vitamins were planned as ‘vitamin B’ depending on the time
of isolation e.g. B1, B2 or Bn. Parallel and false identifications made the system confused. In
addition there were different chemical compounds with the same biological activity. Now it is
known that they are different intermediers of the final active compound therefore they are called
vitamers, e.g. retinol and -carotene or nicotinic acid and nicotinamide (niacin) or cholecalciferol
and ergocalciferol or phylloquinone and menaquinone.
Table 1. Alphabetical name; accepted name; principal fuctions and deficiency diseases of
vitamins
(On the basis of Nutritional biochemistry of the vitamins by D.A. Bender)
Alphabetical name
Accepted name(s) Principal functions
Deficiency diseases
(and
vitamer
precursors)
A
retinol
(and its visual pigments,
night
blindness,
xenophthalmia,
precursor:
- cell differentiation
keratomalacia
carotene)
B1
thiamin (aneurine)
precursor
of beriberi
coenzyme TPP and
role
in
neurotransmission
B2
riboflavin
precursor of redox no distingtive signs
coenzyme FAD
(B3)
niacin (nicotinamide precursor of redox pellagra
and its precursor: coenzymes NAD+
nicotinic acid)
and NADP+
(B5)
pantothenic acid
precursor
of burning
foot
coenzyme A
syndrome
B6
pyridoxin
precursor
of convulsions,
4
(B10)
folic acid
B12
cobalamine
C
ascorbic acid
D
cholecalciferol
(calciol)
-tocopherol (and
its precurors: tocopherol and tocopherol)
biotin
phylloquinon (K1)
and
metaquinon
(K2) (from common
precursor)
E
H
K
coenzyme PAL and
role in steroid action
precursor
of
coenzyme THF
precursor
of
coenzyme
cobalamide
redox
coenzyme
with
oxygen
comsuption
and
anti-oxidant
calcium homeostasis
anti-oxidant
coenzyme
carboxylation
glutamate
postsynthetic
modification
proteins, role
blood coagulation
metabolic
disturbances
megaloblastic
anaemia
anaemia
scurvy
rickets,
osteomalacia
(haemolytic anaemia
of newborn)
rare - skin lesions
of bleeding disorders
in
of
in
Table 2. Alphabetical name; accepted name; name of biologically active derivative and metabolic
function
(On the basis of Nutritional biochemistry of the vitamins by D.A. Bender)
Alphabetical name
Accepted name(s) Name
of Metabolic function
(and
vitamer biologically active
precursors)
derivative
A
retinol
(and its 11-Z-retinal,
the photoisomerisation
absorbing of 11-Z-retinal to
precursor:
- light
group
of
visual all-E-retinal
in
carotene)
pigments
retina
B1
thiamin (aneurine)
thiamin
pyruvate
pyrophosphate
dehydrogenase
(TPP)
multienzyme
complex
B2
riboflavin
flavinadenine
oxidative
dinucleotide (FAD) degradation
of
biomolecules
by
radical mechanism
B3
niacin (nicotinamide nicotinamide
oxidative
and its precursor: adenine dinucleotide degradation
of
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nicotinic acid)
(NAD+)
and
nicotinamide
adenine dinucleotide
phosphate (NADP+)
B5
pantothenic acid
coenzyme A
B6
pyridoxin
pyridoxalphosphate
(PAL)
B10
folic acid
tetrahydrofolic acid
(THF)
B12
C
cobalamin
L-ascorbic acid
cobalamide
L-ascorbic acid
D
cholecalciferol
(calciol)
E
H
K
biomolecules
by
ionic
mechanism
(NAD+)
and
reductive
biosynthetic
processes (NADPH)
central
macroerg
intermediate both in
biosyntheses
and
degradation
processes
elimination
of
amino group in
degradation
of
amino acids, amine
binding function in
active
sites
of
enzymes
transfer
of
C1
fragment
(e.g.
methyl group) on
biomolecules
alkyl rearrangement
coenzyme
in
oxidation by oxygen
and
protection
against
oxidative
damage
together
with -tocopherol
induction
of
osteocalcin,
a
calcium
binding
protein in bone
calcitriol, a hormon
of the metabolism
calcium
and
phosphorous
in
bones
protection against
-tocopherol (and -tocopherol
oxidative
damage
its precurors: together with Ltocopherol and ascorbic acid
tocopherol)
biotin
biotin
rare - skin lesions
phylloquinon (K1) phylloquinon (K1) carboxylation
of
and
metaquinon and
metaquinon glutamate
in
(K2) (from common (K2) (from common postsynthetic
precursor)
precursor)
modification
of
proteins
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Table 3. Alphabetical name of parallel and false vitamin identifications
(On the basis of Nutritional biochemistry of the vitamins by D.A. Bender)
Name of vitamin
Story
B3
Assigned to a compound which was probably pantothenic acid,
nowadays is used for nicotinamide or nicotinic acid (niacin).
B4
Assigned to a mixture of arginine, glycine and cysteine, later
assigned to AMP.
B5
Assigned to a compound which mighth be pyridoxine or nicotinic
acid, now used for pantothenic acid.
B7
Never assigned.
B8
Never assigned.
B9
Earlier used for pantothenic acid.
B10
Assigned to a compound which mighth be a mixture of folic acid
and thiamin, now used for folic acid.
B11
Assigned to a compound which mighth be a mixture of folic acid
and thiamin.
B13
Assigned to orotic acid, that is not vitamin.
B14
Assigned to an unknown substance in urine which increases
proliferation of bone warrow in culture.
B15
Assigned to pangamic acid, its vitamin function was not
established.
B16
Never assigned.
B17
Assigned to a cyanogen glycoside (amygdalin or laetrile) with no
established vitamin function
Bc
Obsolete name for folic acid
Bp
Assigned to ‘anti-perosis’ factor for chikens which can be replaced
by cholin and manganese
BT
Assigned to carnitine which is a grow factor for the meal worm, but
not a vitamin.
Bw
Assigned to a factor which was probably biotin
Bx
Obsolete name for 4-aminobenzoc acid, a precursor of folic acid,
which is not vitamin.
F
Essential fatty acids (linolic acid and linoleic acid) which are not
classified as vitamins.
G
Obsolete name for riboflavin.
H3
Assigned to gerovital which was later identified as novocaine. Not
recognised as a vitamin.
L
Factor in yeast claimed to promote lactation but it was not
established as a vitamin.
M
Obsolete name for folic acid
P
Pharmacologically active bioflavonoids with no vitamin function.
PP
Obsolete name for niacin (pellagra-preventing vitamin).
T
Assigned to a mixture of folic acid, cyanocobalamin and and
nucleotides.
U
Assigned to methylsulphonium salt of methionine which may have
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pharmacological acions, but it is not a vitamin
Nutritional status of vitamins – Determination of essentiality
Before declaring a compound as a vitamin it must be shown to be a dietary essential. That
means its elimination from the diet results in a more or less clearly defined deficiency disease that
can be cured or prevented by adding of this compound to the diet. Only the fact of a
pharmacological action or curing a disease is a necessary condition but not a sufficient evidence
to classify a compound as a vitamin.
Requirements and recommendations
As vitamins are present in foods and in body fluids or tissues in very small amounts (of
the order mol, nmol, even pmol/kg), furthermore they can be exist in multiple chemical forms
(sometimes in biologically unavailable forms), their analysis and the estimation of the useable
vitamin content demand a combination of several chemical and biological methods. With the
modern techniques – e.g. radio-ligand binding assays (radio-immunassay) and hplc techniques –
individual chemical forms of most of the vitamins can be determined with great precision and
specificity. Microbiological and biological assays can be essential to determine the relative
biological activity of different vitamers.
There are several official recommendations for vitamin consumption. On the basis of
population examined recommended intakes are various in different countries. All around the
world accepted lists are Recommended Dietary Allowance (RDA) for an adult man aged between
25-50 for a day from the 1989 US Tables (National Research Council/National Academy of
Sciences, 1989) and Reference Nutrient Intake (RNI) for an adult man aged between 19-50 for a
day from the 1991 UK Tables (Department of Health/Ministry of Agriculture, Fisheries and Food,
1991).
Table 4. Recommended intakes of vitamins
(On the basis of Nutritional biochemistry of the vitamins by D.A. Bender)
Accepted name(s) (and vitamer
RDA (USA)
RNI (UK)
precursors)
1 mg
0.7 mg
retinol (and its precursor: carotene)
thiamin (aneurine)
1.5 mg
1.0 mg
riboflavin
1.7 mg
1.4 mg
niacin (nicotinamide and its
19 mg
17 mg
precursor: nicotinic acid)
pantothenic acid
4-7 mg (average
4-7 mg (average
intake)
intake)
pyridoxin
2.0
1.4
folic acid
0.2 mg
0.2 mg
cobalamin
2.0 g
1.5 g
L-ascorbic acid
60 mg
40 mg
cholecalciferol (calciol)
5 g
10 g (for housebound elderly
8
-tocopherol (and its precurors: tocopherol and -tocopherol)
10 mg
biotin
30-200 g (average
intake)
80 g
phylloquinon (K1) and metaquinon
(K2) (from common precursor)
7 mg (it depends on
intake of polyunsaturated fatty
acids)
30-200 g (average
intake)
70 g
Non-nutritional uses of vitamins
Recommended intakes of vitamins for people the maitenance of normal health and
metabolic integrity and the prevention of deficiency. There are suggestions about the benefit of
vitamins (and other nutritional supplements) intake higher than nutritional requirements. In some
cases no scientific foundations exist and these hypotheses are based only on their
pharmacological action in relatively high intake and speculations. But there are evidences from
medical and laboratory studies that some vitamins may have health benefit in relatively high
doses. For example folic acid supplements in pregnancy is a protective factor against tube defects
and higher intakes of antioxidants (L-ascorbic acid, tocopherols and -carotene) can reduce
probability of cancer and cardiovascular diseases. Nevertheless, several vitamins are acutely or
chronically toxic in high excess (e.g. retinol, cholecalciferol, niacin and pyridoxin).
Vitamin deficiency (avitaminosis and hypovitaminosis)
Vitamin deficiency is a lack of one or more vitamins in humans (or other living
organisms). In the case of hypovitaminosis the level of a vitamin is lower than the recommended
level. In the case of hypervitaminosis the level of a vitamin is higher than recommended level.
There are five vitamins those are associated with a pandemic deficiency disease: niacin (vitamin
B3) – pellagra, ascorbic acid (vitamin C) – scurvy, aneurine (vitamin B1) – beriberi, calciferol
(vitamin D) – rickets, retinol (vitamin A) – night blindness.
Iatrogenic hypovitaminosis
There are drugs with antivitamin actions causing called drug-induced malnutrition. For
example folics antagonists are used in cancer chemotherapy and some of antischizophrenic agents
are riboflavin antagonists. For the normal health smoking persons need more of different vitamins
than non-smoking ones.
The solubility of vitamins
The molecules with apolar character (they can not form no H-bonds with water in most of
the cases because of their non-polarized bonds) are not soluble in water (fat-soluble molecules).
The molecules with polar character (they have polarized bonds e.g. alcohols therefore they can
form H-bonds with water molecules) can be soluble in water (water-soluble molecules).
Vitamins are classified as either water-soluble or fat-soluble. In humans there are 13
vitamins. Ordinary four vitamins (A, D, E and K) are labelled as fat-soluble vitamins but
sometimes vitamins F are mentioned among them. The water-soluble vitamins are the different
vitamins B, vitamin H and vitamin C. Water-soluble vitamins dissolve easily in water, and in
general, are readily excreted from the body, to the degree that urinary output is a strong predictor
9
of vitamin consumption. Because they are not readily stored, consistent daily intake is important.
Many types of water-soluble vitamins are synthesized by bacteria. Water-soluble vitamins are
coenzymes or the starting materials of coenzymes (they are the reagents in the biochemical
reactions). Fat-soluble vitamins are absorbed through the intestinal tract with the help of lipids
(fats). Because they are more likely to accumulate in the body, they are more likely to lead to
hypervitaminosis than are water-soluble vitamins.
Essential polar and apolar characters of simple functional groups
Fat-soluble vitamins
There are two types of lipid (apolar – fatty soluble) biomolecules. Simple lipids cannot be
hydrolyzed by sodium hydroxide and complex lipids can be hydrolyzed by sodium hydroxide.
Fat-soluble vitamins can be stored in the apolar part of cell membranes, sometimes this can cause
hypervitaminosis.
The two main types of simple lipids are the fatty acids and the terpenes. Fatty acids (C16
and C18) are building blocks of complex lipids (neutral triglycerides and phospholipids).
Saturated fatty acids are palmitate (CH3(CH2)14–COOH) and stearate (CH3(CH2)16–COOH).
Unsaturated fatty acids are the unsaturated versions of stearate (C18): oleate, linoleate and
linolenate. The essential linoleate (-6-fatty acid) and linolenate (-3-fatty acid) are known as
PUFA (polyunsaturated fatty acids) or vitamins F. Polyunsaturates fatty acids can be found in
unsaturated oils (oil of fishes, sunflower, flaxseed – linseed, etc.). Essential fatty acids play an
important role in the life and death of cardiac cells.
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Formulas of oleate, linoleate and linolenate
Terpenes can be derived from isoprene (methylbutadiene) CH2=C(CH3)–CH=CH2 (C5H8).
Monoterpenes contain two (C5H8)2 (C10), diterpenes four s (C5H8)4 (C20), triterpenes six (C5H8)6
(C30) and tetraterpenes eight isoprene units (C5H8)8 (C40). The branched end of isoprene is called
the head (fej in Hungarian) and the other part is called the tail (láb in Hungarian). There are
different variations for connecting the isoprene units. Most frequent are head-to-tail connections,
while and tail-to-tail and head-to-head variations are rare. The formation and oxidative
degradation of vitamins with terpene structure are similar to other kinds of terpenes.
H2C
C CH CH2
CH3
izoprén
fej-láb
fej
fej-fej
láb
láb-láb
Az izoprén egységek kapcsolódási fajtái
Different variations of connecting isoprene units: head-to-head, head-to-tail and
tail-to-tail
Calciferols (vitamin D)
The chain of the triterpene squalene can be cyclized to molecule cholesterol. The ring
system of cholesterol is called sterane skeleton (without methyl groups – gonane skeleton).
Cholesterol can be the starting material of different kinds of steroids – among them sexual
hormones. There are different vitamin D molecules – their differences are only in the number of
methyl groups. For example ergocalciferol – vitamin D2 contains an extra methyl group
(compared to cholecalciferol – vitamin D3) at the carbon atom next to the branched carbon atom
and a double bond in the side chain. Vitamin D molecules formed from cholesterol by uv light
play an important role in calcification of cartilage and bone. From vitamin D calcidiol is formed
in the liver then calcitriol in the kidney by hydroxylation. Calcitriol is the biologically active form
of vitamin D.
CH3
CH3
CH3
O
11
CH3 CH3
CH3
CH3
H
The CH
symptoms
of
vitamin
D
are:
brittle
and
CH2
OH fragile bones (rickets), burning in
3
CH
mouth and throat, diarrhea, insomnia,
kámfor
3 CH3 irregular heartbeat, low blood calcium, myopia,
limonén
H
nervousness, pale skin, poor metabolism, rickets,mentol
sensitivity
to pain, soft bones and teeth,
CH2
CH3
OH
osteoporosis and osteopenia,
andmonoterpén
hypocalcemia.
Néhány
mentol D also enhances the immune system.
kámfor képlete Vitamin
limonén
Hypervitaminosis of vitamin D can cause similar symptoms in bones to hypovitaminosis.
Néhány monterpén képlete
Vitamins D can be found in cod liver oil, liver, milk, egg, butter and cheese.
CH3
CH3
CH3
CHCH
3 3
CH
CH3
O
deficiency
CH3
CC
AA
DD
CH
CH3 3 CC
BB
AA
3
CH3
CH3
CH
3
CH
DD
CH3
3
BB
HO
gonánváz
HO
szteránváz
gonánváz
koleszterol
szteránváz
koleszterol
cikloalkánok
cikloalkánok
A gonánváz, a szteránváz és a koleszterol képlete
Formula
of
and sterane
skeletons,
CHgonane
CH3
A gonánváz,
és a3 koleszterol
képleteand cholesterol
3 a szteránváz CH
CH3
CH3
A
HO
CH3
CH3
h
CH3
CH3
h
D
CH2
CH3
CH3
CH3
-jonon
CH3 CH3
(vitamin A)
CH3
CH3
CH3
CH3
CH3
CH3
HOh
-
D3 vitamin (kolekalciferol)
CH2
B
CH3
Retinol
CHD3
CH3
B
CH3 C
A
HO
C
CH3
CH3
hCH3
CH3
CH3
HO
D3-vitamin (kolekalciferol)
CH3
A D3-vitamin keletkezése a koleszterolból
CH3
CH3
ox.
-karotinD3
vitamin
Formation of
CH3
CH3
CH
from cholesterol CH
3
CH3
CH3
CH3
-jonon
CH3
Tetraterpene carotenoides are3 organic pigments that are naturally occurring in the
CH2OH
chloroplasts and chromoplasts of plants. There
are two classes of carotenoides:
i.e.
CH3 hydrocarbons
CH3
CH
CH
3
3
carotenes and xanthophylls
containing oxygen.ox.Because of polyconjugated
double bond system,
CH3 CH3
3
CH3 CH
carotenoids can absorb
light
energy
for
use
in
photosynthesis,
and
as
antioxidants
they protect
-karotin
retinol (A-vitamin)
11-cisz-retinál
CHO-jonon
-jonon
chlorophyll from photodamage. Antioxidants can eliminate free radicals by reduction. In humans
-carotene and other carotenoids can be converted to retinol (vitamin A) by an oxidative
cleavage. Retinal synthesized
fromCH
retinol by oxidation
CH3 is essential for vision.
CHisomerization
CH3 and
3
CH
CH3
CH
3
Night
blindness is3 one of the3 first signs of vitamin A deficiency because its derivative
CH2OH This is a process in which the light is converted
cisz-retinal has a major role in phototransduction.
into electrical signals in the retina of the eye. Vitamin A deficiency also contributes to maternal
mortality and other poor outcomes in pregnancy and lactation.
hypervitaminosis of vitamin A
CHThe
3 CH3
CH
3
can cause liver problems.
retinol (A-vitamin)
11-cisz-retinál CHO
A legismertebb tetraterpén, -karotin és a belôle képzôdô diterpének képlete
cikloalkánok
A gonánváz, a szteránváz és a koleszterol képlete
12
CH3
CH3
CH3
CH3
CH3
CH3
According to a new research CH
vitamin
A stimulates producing of insulin
CH3 that plays an
3
h
CH
C
D
3
important role in the regulation of glucose level. In thisCHway vitamin A deficiency can be a risk
2
factor in forming of type 2 diabetes mellitus.
A
B
Good retinol
source is cod liver oil, and it can be formed by oxidation of their precursor
HO spinach), or by hydrolysis of retinyl esters from the
formsHOcarotenoids from h
plants (e.g. carrot and
D3-vitamin (kolekalciferol)
liver and egg of animals.
A D3-vitamin keletkezése a koleszterolból
CH3
CH3
CH3
-jonon
CH3
CH3
CH3
ox.
-karotin
CH3
CH3
CH3
CH3
CH3
CH3
-jonon
CH3
CH3
CH3
CH3
CH3
CH2OH
CH3
CH3 CH3
retinol (A-vitamin)
11-cisz-retinál
CHO
A legismertebb tetraterpén, -karotin és a belôle képzôdô diterpének képlete
The conjugated double bond system in -carotene and its derivatives
Tocopherols (vitamin E)
Vitamin E is a generic term for tocopherols and tocotrienols (they have three double
bonds in the side chain). Vitamin E is a family of α-, β-, γ-, and δ-tocopherols (they have methyl
groups of different number in different positions) and corresponding four tocotrienols. Vitamin E
is a fat-soluble antioxidant that stops the version of the molecule (containing a quinone structure)
produced in this process may be recycled back to the active reduced form through reduction by
other antioxidants, such as ascorbate (vitamin C) or retinol (vitamin A). Among them
α-tocopherol has been most studied as it has the highest bioavailability.
Vitamin E deficiency causes neurological problems due to poor nerve conduction. It can
also cause anaemia, due to oxidative damage to red blood cells. Its deficiency can cause enlarged
prostate gland, gastrointestinal disease, dry or falling out hair, impotency, miscarriages, muscular
wasting, muscle weakness, sterility. Vitamin E helps prevent cancer, cardiovascular disease,
cataracts and reduces scarring from some wounds. Zinc and Vitamin E work together.
It is supposed that vitamin E in high doses for extended periods increases the risk of
death. Vitamins E can be found in whole grains, seeds and vegetable oils, like sunflower, nuts
and nut oils, like almonds and hazelnuts and some green leafy vegetables.
13
CH3
HO
CH3
CH3
CH3
H3C
O
CH3
CH3
CH3
Az E-vitaminok legismertebb fajtája, az  -tokoferol
Formula of α-tocopherol
The types of tocopherols
Lipid peroxidation is a radical oxidative degradation process of polyunsaturated fatty
acids (PUFA) as linolic acid and linoleic acid (linoleate and linolenate). Lipid peroxidation is a
process mediated by the formation of free radicals at the methylene group(s) between the double
14
bonds of these polyunsaturated fatty acid components of fats and oils, because the hydrogen of
this methylene group is active. The formation of hydroperoxides (>CH–O–O–H), an important
step in lipid peroxidation, is often a simple autoxidation, but an alternative enzymatic reaction
catalyzed by lipoxygenases is also known. Decomposition of hydroperoxides by a radical
mechanism is a complex process that leads to the formation of different short-chain ketones,
aldehydes and carboxylic acids with an unpleasant odour or flavour and to dialdehydes. Besides
the important role that lipid peroxidation plays in flavour deterioration and rancidity in food and
food raw materials, there is also considerable interest in its role and the role of other free radical
reactions in human diseases (e.g. arteriosclerosis, myocardial infarction and cancer). Lipid
peroxidation can be prevented by the help of antioxidant vitamins, especially by tocopherols
because of their apolar character.
Vitamin K
Vitamin K is a group of hydrophobic vitamins that are needed for the posttranslational
modification of certain proteins (e.g. protrombin), mostly required for blood coagulation but also
involved in metabolism pathways in bone and other tissue. They are 2-methyl-1,4naphthoquinone derivatives.
As vitamin K is an important factor of the cascade system of blood clotting, its deficiency
can cause low platelet count in blood and poor blood clotting later on serious haemophilia. There
is physiological and observational evidence that vitamin K plays a role in bone growth and the
maintenance of bone density. Its deficiency can cause brittle or fragile bones. The efforts to delay
the onset of osteoporosis by vitamin K supplementation have proven ineffective, but it is
supposed that vitamin K can help to prevent osteoporosis. It is supposed that vitamin K,
especially K2 plays an important role in the formation of osteocalcin that is one of the proteins in
the bones. This protein is responsible for the infiltration of calcium into the bones. Vitamin K
also converts glucose into glycogen for storage in the liver therefore its deficiency can cause a
high glucose level in blood.
Vitamin K1 is also known as phylloquinone. vitamin K2 (menaquinone) (containing three
double bond in side chain) is normally produced by bacteria in the large intestine, therefore
dietary deficiency is extremely rare unless the intestines are heavily damaged, are unable to
absorb the molecule, or are subject to decreased production by normal flora, as seen in broad
spectrum antibiotic use. Vitamin K1 can be found in foods with plant original (in leafy green
vegetables such as spinach and Brassica: e.g. cabbage, cauliflower, broccoli, and brussels
sprouts) and vitamin K2 can be found in foods with animal original (e.g. liver). Bacteria in the
large intestine can form vitamin K2 from vitamin K1.
O
CH3
CH3
CH3
CH3
CH3
CH3
O
Az K-vitaminok legismertebb fajtája, a K1-vitamin
15
Formula of vitamin K1 – phylloquinone
Water-soluble vitamins
Water soluble vitamins are starting materials of most of the compounds with coenzyme
function. Oxidoreductases and transferases need reagents (compounds with coenzyme function)
for the catalyzed reactions. Compounds with coenzyme function (henceforth they are called as
coenzymes) are connected to enzymes either by secondary bonds (they are really coenzymes –
they can be regenerated also in other reactions) or by covalent bonds (prosthetic groups – they can
be regenerated only in their original place). Compounds with coenzyme function have two forms
(unreacted and reacted) – only lipoic acid has three forms. The starting materials for coenzymes
are water-soluble vitamins and in a few cases essential amino acids.
Coenzymes for oxidoreductases
In primary metabolism oxidoreductases are always dehydrogenases, because the
reoxidation of reduced coenzymes is connected with the producing of energy in form of macroerg
bonds in respiratory chain (mitochondrial electron transport chain of terminal oxidation). The
mechanism of these oxidoreductase coenzymes can be ionic (hydrogen molecules are transported
as hydride anions and protons) or radical (one hydrogen molecule is transported in form of two
hydrogen atoms).
In the oxidative destroying processes of catabolism NAD+ (its starting material is
nicotinamide i.e. vitamin B3) – its reduced form is (NADH+H+) (nicotinamide adenine
dinucleotide) involve an ionic, while FAD (its starting material is riboflavine i.e. vitamin B2) – its
reduced form is FADH2 (flavin adenine dinucteotide) and FMN – its reduced form is FMNH2
(flavin mononucleotide) a radical mechanism. FMN takes part only in terminal oxidation. In
reductive biosyntheses of anabolism the coenzyme is (NADPH+H+) in both mechanisms. The
difference between NAD+ NADP+ is the presence of a phosphoryl group on the C-2 hydroxyl
group of ribose in NADP+. Flavin-containing coenzymes are always prosthetic groups. Nicotinic
acid is one of the chelating compounds in glucose tolerance factor forming an organic chromium
complex.
Niacin (vitamin B3)
Niacin (also known as vitamin B3, nicotinic acid and vitamin PP) is water-soluble solid
pyridine derivative with a carboxyl group (COOH) at the 3-position. Other forms of vitamin B3
include the corresponding amide, nicotinamide ("niacinamide"), where the carboxyl group has
been replaced by a carboxamide group (CONH2). The terms niacin, nicotinamide, and vitamin B3
are often used interchangeably to refer to any member of this family of compounds, since they
have the same biochemical activity. Niacin cannot be directly converted to nicotinamide but both
compounds could be converted to NAD+ and NADP+ in vivo (in the living organisms).
The name of niacin is a generic term for two vitamers nicotinic acid and nicotinamide.
The essential compound is nicotinic acid that is the precursor of nicotinamide. This amide
derivative is the precursor of NAD+ and NADP+. Nicotinic acid is the only vitamin that was
discovered by chemical synthesis: by oxidation of nicotine in 1867. Its name comes from the
name of tobacco alkaloid nicotin after Jean Nicot, French Ambassador who was one of the first to
grow tobacco in Portugal in the 16th century. Its metabolic function was recognized when NAD+
and NADP+ was discovered in the first decades of the 20th century. There was confusion in the
16
literature in connection with the name. The original compound name is connected to tobacco and
smoking so it can be associated with an unhealthy activity. Therefore name ‘niacin’ was
suggested. But in the North American usage name ‘niacin’ is specially nicotinic acid and
nicotinamide is known as ‘niacinamide’. Later it was proved that niacin could be synthesized in
the body from tryptophan (if the level of pyridoxine – vitamin B6 is high enough), nevertheless,
for historical reasons it is classified as a vitamin.
H
H
H
HO
H
O
CONH2
HN
HN
N
CONH2
NH
+ H
O
N
H
(DHU)
= 260dihidro–uracil
nm
HOCH2O
O
O
N
H
H
H
H
max = 260 és 340 nm
max
OH OH
pszeudo
uridin (C)
A nikotinamidot tartalmazó koenzimek redukálódási
folyamata
Néhány ritka nukleotid képlete
The process of reduction of coenzymes containing a nicotinamide structure
H
H
H
CONH2
CONH2
CH2
O
H
CH2
N
O
O
H
H
H
OH OH NH2
N
P
O
P
O
H
H
N
N
N
O
CH2
2H (H + H )
P
N
O
H
H
H
OH OH NH2
N
H
O
P
O
H
H
H
OH OR
+
R = H (NAD ) nikotinamid-adenin-dinukleotid
R = P (NADP+ )
N
N
N
O
CH2
H
H
H
H
OH OR
R = H (NADH + H+ )
R = P (NADPH + H+ )
A NAD+ és NADP+ koenzimek
Coenzymes NAD+ and NADPH+
17
Hydride anion from its reduced form (NADH+H+) is the reducing agent in reductive
(energy-demanding) biosyntheses of biomolecules by both ionic and radical mechanism.
Reduction (regeneration) of NADP+ is in catabolic pentose phosphate pathway (hexose phosphate
shunt) that is an alternative oxidative degradation of glucose to pentoses and CO2. NAD+ and
NADP+ coenzymes are often referred to as the pyridine nucleotide coenzymes and their notation
is NAD(P+). These coenzyme are often mentioned as NAD(P) without notation of their charge.
During reduction by hydride anion C-4 of pyridine ring results in a saturated carbon (sp3 hybrid
status) and these hydrogen atoms are above and below of the plane of heterocyclic ring.
As the aromatic ring systems both pyridine and purine ring of NAD+ or NADP+
coenzymes have an absorption peak at 260 nm. Because of the quinon-like structure of the partly
saturated pyridine ring of their reduced form they have an absorption peak at 340 nm, as well.
Therefore the activity of dehydrogenase enzymes using pyridine nucleotide coenzymes can be
measured easily by spectrophotometric way. Their molar absorption coefficient is 6220 in water.
Moreover, these coenzymes can be used also for enzymic concentration determination of different
biomolecules. For example the glucose concentration of an aqueous solution can be measured by
a system containing hexokinase, glucose-6-phosphate dehydrogenase and NADP+. Different
diagnostic kits are available for medical analyses containing pyridine nucleotide coenzymes.
The absorption diagrams of NAD+ and (NADH+H+)
In maize the most of niacin content is biologically unavailable because it is bound to
polysaccharides, polypeptides and glycopeptides with ester bond. The name of nicotinoyl esters
of these macromolecules (ranging between 1500-17 000 D) is niacytin. It was found that less than
10% of the total niacin content of maize is biologically available as a result of hydrolysis by
gastric acid. The treatment of cereals with alkali (e.g. soaking overnight in calcium hydroxide
solution, as is the traditional method for the preparation tortillas in Mexico and baking with
alkaline baking powder releases much of the nicotinic acid. This may explain why avitaminosis of
niacin (pellagra) is has always been rare in Mexico despite the fact that maize is the most
important food there. During roasting of whole grain maize, that is popcorn, the ammonia
released from glutamine can form free nicotinamide by ammonolysis.
Vitamin B3 deficiency occurs mostly in developing countries but it can be found also in
developed countries. The symptoms of the avitaminosis of vitamin B3 – pellagra are dry hair, eye
18
sties, fatigue, insomnia, impaired growth, itching and burning eyes (high sensitivity for sunlight),
loss of smell, dry skin, sinus trouble, weakness, diarrhea, eventually dementia. Because of the
decreased immune system function, the cancer susceptibility is increased.
Vitamin B3 can be found in fish and liver, cereals, green and yellow fruits and vegetables,
Apricots, asparagus, beets, broccoli, butter, cantaloupe, carrots, cheese, garlic, green olives, milk
products, mustard (fresh), papaya, parsley, peaches, prunes, red peppers, sweet potatoes, spinach,
sweet potatoes, pumpkin and watercress.
In plants the starting materials of niacin are D-glicerinaldehyde-3-phosphate and
L-aspartic acid. In animals and human persons the starting material is L-tryptophane. From
intermediate dicarboxylic acid quinolinic acid NAD+ and NADP+) is synthesized in several steps
in a cycle. Into this cycle can enter niacin (nicotinic acid or nicotinamide). During the degradation
of nicotinic acid ammonia and different carboxylates are formed.
19
Riboflavin (vitamin B2)
Riboflavin, also known as vitamin B2, is an easily absorbed micronutrient with a key role
in maintaining health in humans and animals. As it was mentioned it is the central component of
the coenzymes FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2
is required for a wide variety of cellular processes. Like the other B vitamins, it plays a key role in
energy metabolism, and for the metabolism of fats, ketone bodies, carbohydrates, and proteins.
H
N
N
2H
N
N
H
A flavint tartalmazó koenzimek redukálódási folyamata
The process of reduction of coenzymes containing flavines
The name "riboflavin" comes from "ribose" (the sugar which forms part of its structure,
and flavin, the ring-moiety which imparts the yellow color to the oxidized molecule (from Latin
flavus, "yellow"). The reduced form, which occurs in metabolism, is colorless. Riboflavin is best
known visually as the vitamin which imparts the orange color to solid B-vitamin preparations, the
yellow color to vitamin supplement solutions, and the unusual fluorescent yellow color to the
urine of persons who supplement with high-dose B-complex preparations (no other vitamin
imparts any color to urine).
20
O
H3C
H3C
N
H
NH
N
N
O
H3C
N
H3C
N
N
CH2
H
NH
2H
O
CH2
NH2
HCOH
HCOH
H
HCOH
H2C O
P
O
H
H
N
N
O
P O CH2
H
H
N
N
HCOH
N
N
O
H2C O P O P O CH2
NH2
HCOH
N
N
HCOH
O
H
H
H
OH OH
OH OH
FADH2
FAD (flavin-adenin-dinukleotid)
O
H3C
N
H3C
N
NH
N
CH2
HCOH
O
R = P FMN (flavin mononukleotid)
R = H (B2 vitamin) riboflavin
HCOH
HCOH
H2C O–R
A flavint tartalmazó koenzimek és prekurzor vitaminjuk
Flavin-containing coenzymes and their precursor vitamin
Riboflavin is continuously excreted in the urine of healthy individuals, making deficiency
relatively common when dietary intake is insufficient. However, riboflavin deficiency is always
accompanied by deficiency of other vitamins. A deficiency of riboflavin can be primary – poor
vitamin sources in one's daily diet – or secondary, which may be a result of conditions that affect
absorption in the intestine, the body not being able to use the vitamin, or an increase in the
excretion of the vitamin from the body.
In humans, signs and symptoms of riboflavin deficiency include cracked and red lips,
inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the mouth,
and a sore throat. A deficiency may also cause dry and scaling skin, fluid in the mucous
membranes, and iron-deficiency anemia. The eyes may also become bloodshot, itchy, watery and
sensitive to bright light. Riboflavin deficiency is classically associated with the
oral-ocular-genital syndrome. Angular cheilitis, photophobia, and scrotal dermatitis are the classic
remembered signs. Although the effects of long-term subclinical riboflavin deficiency are
unknown, in children this deficiency results in reduced growth. Subclinical riboflavin deficiency
has also been observed in women taking oral contraceptives, in the elderly, in people with eating
disorders, and in disease states such as HIV, inflammatory bowel disease, diabetes and chronic
heart disease. The fact that riboflavin deficiency does not immediately lead to gross clinical
manifestations indicates that the systemic levels of this essential vitamin are tightly regulated.
21
Vitamin B2 can be found in milk, cheese, leafy green vegetables, liver, kidneys, legumes,
tomatoes, yeast, mushrooms, and almonds are good sources of vitamin B2, but exposure to light
destroys riboflavin.
The starting material of riboflavin is GTP, the ribitol part of the molecule is comes from
ribose of GTP. The dimethylbenzene fraction of the ring system is derived from the tetrolose
phosphate (C4). From riboflavin one of the intermediate (5,6-dimethyl-benzimidazole) of vitamin
B12 can be formed. The ring system of riboflavin can be illustrated in two different ways – with
the pyrimidine ring on the left or the right side of the molecule.
22
The biosynthesis of riboflavin
L-Ascorbic acid (ascorbate, vitamin C)
23
The coenzyme of direct oxygenases is ascorbic acid (ascorbate, vitamin C). It is a
coenzyme in at least eight enzymatic reactions, including several collagen synthesis reactions that
cause the most severe symptoms of scurvy when they are dysfunctional. In animals, these
reactions are especially important in wound-healing and in preventing bleeding from capillaries.
One of secondary structures of peptide chains is collagen structure. Collagen structure contains
three of left-handed extended helical polypeptide chains rolled into a cable form of a right-handed
helix. In tropocollagen units are Gly-Pro-Hyp triplets, hydroxyproline (Hyp) is synthesized by a
direct oxidation of proline in peptide chain by means of L-ascorbate).
O
N
O
N
1/2 O2
(az aszkorbinsav
közvetítésével)
HO
Hyp részlet a
Pro részlet a
fehérjeláncban
fehérjeláncban
A hidroxi-prolin képzôdése a peptidláncban
Oxidation of proline to hydroxyproline in the peptide chain by L-ascorbate (vitamin C)
Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the
synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from
the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic ("of,
characterized by or having to do with scurvy"). Scurvy leads to the formation of spots on the skin,
spongy gums, and bleeding from the mucous membranes. The spots are most abundant on the
thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially
immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth.
In living organisms, ascorbate is also an antioxidant, since it protects the body against
oxidative stress. Oxidative stress creates free radicals and antioxidants can eliminate free radicals
by reduction. Ascorbic acid is well known for its antioxidant activity, acting as a reducing agent
to reverse oxidation in liquids. When there are more free radicals (reactive oxygen species, ROS)
in the human body than antioxidants, the condition is called oxidative stress, and has an impact
on cardiovascular disease, hypertension, chronic inflammatory diseases, and diabetes as well as
on critically ill patients and individuals with severe burns. There is some evidence that it reduces
symptom severity but not incidence of the common cold. Vitamin C helps prevent infection,
enhances immunology and can help prevent cancer.
24
Formation, oxidation and stability of ascorbic acid
Almost all organisms can synthesize ascorbic acid; except some mammalian groups
(among them monkeys, apes and human beings). Ascorbic acid can not be synthesized also by
guinea pigs, capybaras, and some species of birds and fish. The starting material of the
biosynthesis of ascorbic acid is UDP-glucose that is also the the starting material of different
kinds of glucosides (e.g. sucrose). After its oxidation and hydrolysis D-glucuronic acid is formed
that is oxidized to L-gulonic acid then after cyclization L-gulonolacton. The last step of ascorbate
biosynthesis is the oxidation of L-gulonolacton by oxygen. Humans, some other primates, and
guinea pigs are not able to synthesize L-gulonolactone oxidase because of a genetic mutation and
are therefore unable to make ascorbic acid. Therefore ascorbic acid is essential for them and they
require it in the diet.
While plants are generally a good source of vitamin C, the amount in foods of plant origin
depends on the precise variety of the plant, soil condition, climate where it grew, length of time
since it was picked, storage conditions, and method of preparation. The richest natural sources are
fruits and vegetables, and of those, the Kakadu plum and rose hip contain the highest
25
concentration of the vitamin. It is also present in some cuts of meat, especially liver. There are
also alternative routes in plants for ascorbate biosynthesis (e.g. L-galactose pathway).
O
O
HO
ox
O
red
HO
O
O
O
HO C H
CH2OH
H
HO C
CH2OH
L-aszkorbinsav
dehidro-aszkorbinsav
(bomlékony)
(C-vitamin)
Az aszkorbinsav oxidált és redukált formája
Redox reactions of L-ascorbic acid
NH2
N
The oxidation product of ascorbic acidNis dehydro-L-ascorbic
acid in a reaction of radical
mechanism. The balance of opening and closure reaction of the ring of lactons is known. But the
product of the opening reaction of dehydroascorbic
acid
N can not take part in a ring closure
N
reaction. It can be oxidized
to oxalic acid and tartarate. Therefore the ascorbate level of food raw
P–O–P–O–P–CH
O
2
materials with plant origin decreases during storage or producing foods.
H
H
H
H
OH
OH
Az ATP átadható csoportjai
Oxidative degradation of ascorbic acid to oxalic acid and tartarate
Other molecules with coenzyme function for oxidoreductases
There are three other coenzymes of oxidoreductases but their starting materials are not
water soluble vitamins.
Ubiquinone (coenzyme Q) (its starting material is tyrosine and its reduced form is
ubiquinol) is that kind of oxidoreductase coenzyme, which can work by both ionic and radical
mechanism. This is an important participant of the mitochondrial electron transport in respiratory
chain. The name of the human ubiquinone is CoQ10. Nowadays it is a popular food additive.
26
Redox reactions of ubiquinone
In various kinds of cytochrome proteins can play an important role in different kinds of
electron transport. Their prosthetic group for electron transfer is heme group (by ferrous-ferric
transformation). A heme group consists of an iron (Fe) ion (charged atom) held in a heterocyclic
ring, known as a porphyrin. This porphyrin ring consists of four pyrrole molecules cyclically
linked together with the iron ion bound in the centre. The iron ion, which is the site of oxygen
binding, coordinates with the four nitrogen atoms in the centre of the ring, which all lie in one
plane. It is mentioned that in hemoglobin transporting oxygen in blood the iron ion is always in
ferrous form in heme because of the special connection between heme group and proteins. Heme
is one of the starting materials of cobalamin (vitamin B12) and chorophylls. The starting material
of the ring system is 5-aminolevulinate synthesized from different amino acids of different living
organisms.
The structure of heme
Lipoic acid is a prosthetic group for both oxidoreductase and transferase function. That is
connected to the -amino group of a lysine of the enzyme. It can be acetylated by active
acetaldehyde with an oxidative reaction followed by an acyl transfer to coenzyme A. The details
are given at vitamin B1 and B5. The precursor to lipoic acid, octanoic acid, is made via fatty acid
biosynthesis.
27
COOH
COOH
S
HS
S
liponsav
SH
dihidro-liponsav
COOH
HS
S C CH3
O
acetil-dihidro-liponsav
A liponsav koenzim különbözô formái
Three forms of lipoic acid
Coenzymes for transferases
Transferases can catalyze several kinds of substitutions. The transferred groups can be
different carbon skeletons: C1 – CO2 (biotin that is vitamin H), only methyl group (SAM – Sadenosylmethionine, its starting material is methionine), methyl group, aldehyde group, etc. (THF
– tetrahydrofolate, its starting material is folic acid i.e. vitamin B9); C2 – acetaldehyde (TPP –
thiamine pyrophosphate, its staring material is aneurine, i.e. vitamin B1), acetyl group in a
macroerg thiolester bond (coenzyme A, its starting material is panthotenic acid, i.e. vitamin B5);
and other groups: phosphate group (ATP or other nucleoside triphosphate molecules), amino
group (PAL – pyridoxal phosphate, its reacted form is PAM – pyridoxamine phosphate, and its
starting material is pyridoxine i.e. vitamin B6).
Transfer of C1 components
Biotin (vitamin H, vitamin B7)
O
HN
C
S
ATP
O
ADP
HOOC
NH
CH2
CH2
biotin
(H-vitamin)
CH2
CH2
N
C
CO2
COOH
S
NH
CH2
CH2
CH2
CH2
COOH
karboxi-biotin
A biotin keletkezése és formái
Carboxylation of biotin
Biotin is the coenzyme of carboxylation. From the name vitamin H the H represents ‘Haar
und Haut’ – these are German words for hair and skin. The water-soluble vitamin is composed of
an ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene. Its side chain is a valeric
acid (C5). Biotin is a coenzyme of the addition of a molecule CO2 (carboxylating agent) in
gluconeogenesis, and also in the metabolism of fatty acids and leucine. The first step is the
formation of an active CO2 complex by means of ATP followed by the carboxylation of one of
28
the nitrogen of biotin. Biotin binds very tightly to the tetrameric protein avidin deposited in the
whites of the eggs of birds, reptiles and amphibians (e.g. frogs and toads).
Biotin is consumed from a wide range of food sources in the diet, however there are few
particularly rich sources. Foods with relatively high biotin content include egg yolk, liver, and
some vegetables. Biotin deficiency is relatively rare and mild, and can be addressed with
supplementation. Such deficiency can be caused by the excessive consumption (e.g. 20 eggs in a
day) of raw egg whites because of their high avidin content. Avidin can be deactivated by
cooking, while the biotin remains intact. Symptoms of biotin deficiency are hair loss,
conjunctivitis and dermatitis.
Pregnant women tend to have high risk of biotin deficiency. Research has shown that
nearly half of pregnant women have an abnormal increase of 3-hydroxyisovaleric acid, which
reflects reduced status of biotin. Numbers of studies reported that this possible biotin deficiency
during the pregnancy may cause infants' congenital malformations such as cleft palate (this is a
split on the roof of the mouth). It is suggested that Cot Death (Sudden Infant Death Syndrome)
may be due to a marginal biotin deficiency. It is supposed that in the case of a modest metabolic
stress (e.g. a mild fever) causes a higher requirement of gluconeogenesis. In the case of low biotin
concentration this can cause acute hypoglycaemia.
Biotin is synthesized from alanine and pimeoyl CoA (HOOC-(CH2)5-CO-CoA) in several
steps. Sulfur atom derives from a methionine in the last step of the synthesis.
Folic acid (vitamin B9)
CH2
O
H
4
H2N
CH2–NH
N
5
HN 3
2
C1
6
8 7
1
N
CH
4-aminobenzoesav
N
COOH
COHN
H
tetrahidro-folsav (THF)
C 1:
CHO
CH2
CH3
CH2
CH2OH
COOH
Glu
O
N
HN
H2N
N
CH2–NH
COOH
COHN
CH
CH2
N
folsav (B10 vitamin)
CH2
COOH
A C1 részleteket szállító koenzim és prekoenzim vitaminja
Transfer coenzyme – C1 – THF
Tetrahydrofolic acid (tetrahydrofolate, THF) is the coenzyme of transferases catalyzing
the transfer of different C1 fragments –methyl, aldehyde, methylene and hydroxymethyl groups.
29
Folic acid (also known as folate, folacin or vitamin B9) is a typical example for the confusion in
the nomination of vitamin B types. Originally pantothenic acid was called vitamin B9. At that
time the name of folic acid was vitamin B10. Now 4-aminobenzoic acid (para-aminobenzoic acid,
PABA), a part of folic acid is vitamin B10, and folic acid is named vitamin B9.
30
Biosynthesis of folic acid
Folic acid is itself not biologically active, but its biological importance is due to
tetrahydrofolate and other derivatives after the reduction of folic acid to dihydrofolic acid in the
31
liver. The name of folic acid and its derivatives comes from the Latin word folium (which means
leaf). Leafy vegetables are a principal source, although, in Western diets, fortified cereals and
bread may be a larger dietary source. Folic acid contains pterin ring system.
Folic acid can be found in beans, beef, bran, barley, brown rice, cheese, chicken, dates,
green leafy vegetables, lamb, lentils, liver, milk, oranges, organ meats (like liver), split peas,
pork, root vegetables (like carrots), salmon, tuna, whole grains, whole wheat and yeast.
The starting material of folic acid is GTP from that dihydropteroic acid is synthesised
after several steps. This intermediate reacts with glutamic acid to give dihydrofolic acid that is
reduced to THF. Folic acid that is essential for mammalians. THF is synthesised from vitamin B9
in two consecutive reducing steps.
The deficiency symptoms of folic acids are sore tongue, B12 deficiency, depression or
anxiety, fatigue, and birth defects in pregnant women. Folic acid is needed for energy production,
protein metabolism, the formation of red blood cells and it vital for normal growth and
development.
THF is the most important methylating agent in the living organisms. It is involved in the
synthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′phosphate). It is a substrate for an important reaction that involves vitamin B12 and it is necessary
for the synthesis of DNA, and so required for all dividing cells. Therefore THF can cause birth
defects in pregnant women. Methylene-THF is formed from THF and a C1 donor ( formaldehyde,
serine or glycine). Methyl-THF can be formed from methylene THF by a reduction with
(NADPH+H+). Vitamin B12 is the only acceptor of methyl-THF. And homocystein is also only
acceptor for methyl-B12. This reaction results in methionine and catalyzed by homocysteine
methyltransferase. This is important because a defect in homocysteine methyltransferase or a
deficiency of B12 can lead to a methyl-trap of THF and a subsequent deficiency. Thus, a
deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and
will mimic folate deficiency.
32
NH2
H2N
COOH
CH2
O
P
P
P –O–CH2
O
CH2
H
OH
CH3
Met
Pi
PPi
N
H
H
+
OH
ATP
COOH
N
N
CH2
S
CH3
NH2
CH
CH2
H3C
N
O
H
S
H2N
N
N
CH
CH2
H
H
N
N
O
H2N
COOH
NH2
CH
CH2
CH2
S
N
N
H
H
H
OH OH
S-adenozil-metionin (SAM)
N
N
O
CH2
H
H
H
OH
OH
S-adenozil-homocisztein (SAH)
A SAM keletkezése és különbözô formái
Demethylation process of methionine to homocysteine
From methionine and ATP S-adenosyl methionine (SAM) is formed. SAM is a coenzyme
of ionic methylation of hydroxy and amino groups. When SAM looses the methyl cation Sadenosyl homocysteine is formed. After its hydrolysis to homocysteine and adenosine methionine
can be regenerated by the reaction of homocysteine and methyl-THF. Homocysteine is the
starting material of cysteine in animals and humans. The intermediate of this biosynthesis is
cystathionine. The energy of this synthesis is from the macroerg bond of succinyl-CoA. The
formation of cysteine is connected with an intermolecular oxidation (on homocysteine part
cystathionine) and reduction (between sulphur and the side chain of homocysteine) followed by
the hydrolysis of imino-acid resulting in cysteine and -ketobutyrate. In this way in animals and
humans cysteine is synthesized from methionine. In plants methionine is synthesized from
homocysteine that is formed by another degradation of cystathionine made from homoserine and
cysteine. This degradation results in homocysteine and pyruvate.
33
Forming of cysteine from homocysteine in animals and humans
34
In the case of some trouble in sulphur containing amino acid (about 20-30% of people)
can increase the concentration of homocysteine. A high level of blood serum homocysteine
"homocysteinemia" is a powerful risk factor for cardiovascular disease. Homocysteine in high
concentration can take part in auto-oxidation and react with reactive oxygen intermediates. This
can cause damage in endothelial cells and a higher risk to form a thrombus. Elevated levels of
homocysteine can increase the possibility of fractures in elderly persons. Homocysteine does not
affect bone density. It is supposed that it can influence the structure of collagen.
As it was mentioned the 4-aminobenzoic acid (para-aminobenzoic acid, PABA) part of
folic acid is considered as a vitamin (vitamin B10). It is sometimes referred as vitamin Bx. PABA
is an intermediate in the bacterial synthesis of folic acid. Some bacteria in the human intestinal
tract such as Escherichia coli require PABA. Humans require folate since we lack the enzymes to
convert PABA to folate. Therefore, in humans, PABA is not a vitamin and is considered nonessential. Despite the lack of any recognized syndromes of PABA deficiency in humans, many
claims of benefit are made by commercial suppliers of PABA as a nutritional supplement. Benefit
is claimed for fatigue, irritability, depression, weeping eczema (moist eczema), scleroderma
(premature hardening of skin), patchy pigment loss in skin (vitiligo), and premature grey hair.
Oral supplements of PABA can make the skin less sensitive to sun damage. PABA is largely nontoxic, but allergic reactions can occur. PABA is formed in the metabolism of certain ester local
anesthetics, and many allergic reactions to local anesthetics are the result of reactions to PABA.
The similarity between 4-aminobenzoic acid in amide bond (H2N–C6H5–CONH–) and
sulfonamide (H2N–C6H5–SO2NH–) containing drugs is an excellent example for the importance
of bioisosteres. According to the chemical definition the bioisostere is a compound resulting from
the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of
atoms. The objective of a bioisosteric replacement is to create a new compound with similar
biological properties to the parent compound. The bioisosteric replacement may be
physicochemically or topologically based.
35
In medicinal chemistry, bioisosteres are substituents or groups with similar physical or
chemical properties that impart similar biological properties to a chemical compound. In drug
design, the purpose of exchanging one bioisostere for another is to enhance the desired biological
or physical properties of a compound without making significant changes in chemical structure.
The main use of this term and it techniques are related to pharmaceutical sciences.
Bioisosteres can connect to an acceptor or a substrate binding site in competition with the
original substrate, but in most of the cases this complex formed can not execute the function of
the complex with the original substrate, therefore an antagonism or inhibition can be found.
Sulphonamide drugs are structurally similar to PABA, and their antibacterial activity is due to
their ability to interfere with the conversion of PABA to folic acid by the enzyme dihydropteroate
synthetase. From the sulphonamide analogue of dihydrofolic acid THF can not be synthesized. In
this way bacterial growth is limited through folic acid deficiency without effect on human cells.
At the time of the Second World War sulphonamides saved of the numberless American soldiers
from the bacterial infections. Later on bacteria became resistant to sulphonamides and penicillin
derivatives pushed out their medical use. Nowadays a combination of sulphonamides and
trimethoprim (a good inhibitor of dihydrofolate reductase) is used because of their synergism. The
synergism is an interaction of discrete agencies (as industrial firms), agents (as drugs), or
conditions such that the total effect is greater than the sum of the individual effects.
Cobalamine (vitamin B12)
Vitamin B12 consists of a class of chemically-related compounds (vitamers) with vitamin
activity. It contains the biochemically rare element cobalt. Biosynthesis of the basic structure of
the vitamin in nature is only accomplished by simple organisms such as some bacteria and algae,
but conversion between different forms of the vitamin can be accomplished in the human body. A
common synthetic form of vitamin B12 is cyanocobalamin. This synthetic material is used in
vitamin combinations because of its stability and lower cost. In the body it is converted to the
physiological forms methylcobalamin and adenosylcobalamin instead of cyanide group.
Hydroxycobalamin produced by bacteria is also can be used. The starting materials of vitamin B12
are heme group and one of the intermediates (5,6-dimethyl-benzimidazole) of riboflavin
biosynthesis.
The
transfer
coenzyme
of
alkyl
groups
is
adenosylcobalamin
(5'deoxyadenosylcobalamin), that is the coenzyme of methylmalonyl coenzyme A mutase. It takes
part in the oxidative degradation of fatty acids having an odd number of carbon atoms (these are
minor species). In this case the end product of the -oxidation of fatty acids is one molecule of
propionyl CoA instead of acetyl-CoA. This molecule is converted to succinyl CoA (an
intermediate of citric acid cycle) in two steps (carboxylation followed by an intramolecular
rearrangement). This process is catalysed by methylmalonyl coenzyme A mutase.
Methylcobalamine is the coenzyme of the change of a methyl group between methyl-THF and
homocysteine catalyzed by5-methyltetrahydrofolate-homocysteine methyltransferase.
36
H2NOCCH2 H3C H3C H3C CH2CONH2
H2NOCCH2
C
CH2CH2CONH2
A
B
H3C
N CN N
H3C
Co
CH
N
N
CH3
H2NOCCH2
D
C
CH3
O=C–CH2CH2
C
CH2CH2CONH2
NH
CH3
CH3
CH2–CH–O
O
CH3
P
N
OH
CH3 O
O
N
HOCH2
CH3
O
A B12 vitamin képlete
Cyanocobalamin
As it was mentioned earlier the action of together folic acid and cobalamin is needed for
methylating reactions therefore some of deficiency symptoms are common. Symptoms of
deficiency of vitamin B12 are appetite loss, diminished reflex responses, fatigue, irritability,
memory impairment, mental depression and confusion, nervousness, pernicious anemia
(megaloblastic anaemia – because of the inhibition of DNA synthesis in red blood cells),
unpleasant body odor, walking and speaking difficulties, weakness in arms and legs. A deficiency
can cause problems with digestion, absorption of food, metabolism of carbohydrates and fats,
nerves, fertility, growth and development. There can also be hallucinations, memory loss, eye
disorders, and anemia. A vitamin B12 deficiency can indicate there is a problem with absorption
(common in people with digestive disorders).
The sources of vitamin B12 are all animal sources: beef, blue cheese, cheese, clams, crab,
fish, eggs, herring, kidney, liver, mackerel, milk and milk products, pork, seafood and tofu,
therefore vega (vegetarian) persons need supplement of vitamin B12. In the case of a long lasting
alcoholism vitamin B12 absorption can be decreased from the gastrointestinal tract.
Transfer of C2 components
Thiamine (aneurine, vitamin B1)
The name of thiamine comes from thio-vitamin that is sulphur-containing vitamin. The name of
aneurin comes from one of deficiency symptoms (detrimental neurological effects). Its phosphate
derivatives are involved in many cellular processes. The coenzyme derived from vitamin B1 is
thiamine pyrophosphate (TPP), a coenzyme of the transfer of acetaldehyde in the catabolism of
sugars (coenzyme of pyruvate dehydrogenase multienzyme complex) and the metabolism of
37
amino acids. In yeast, TPP is also required in the first step of alcoholic fermentation. The name of
TPP substituted with acetaldehyde is active acetaldehyde.
H3C
CH2CH2O
N
H3C
CH2 N
NH2
O
P
H3C
H3C
CH2 N
C
N
tiamin-pirofoszfát (TPP)
H3C
O
P
S
CH2CH2OH
CH2 N
CH
N
P
NH2 H3C C OH
H "aktív acetaldehid"
N
H3C
CH2CH2O
N
S
CH
N
P
S
NH2
tiamin (aneurin) B1-vitamin
Az acetaldehidet szállító koenzim és prekurzor vitaminja
Transfer coenzyme – acetaldehyde – TPP
O
HN
C
S
ATP
O
ADP
HOOC
NH
CH2
CH2
biotin
(H-vitamin)
CH2
CH2
N
C
CO 2
COOH
S
NH
CH2
CH2
CH2
CH2
COOH
karboxi-biotin
A biotin keletkezése és formái
The reaction catalyzed by pyruvate dehydrogenase
Active acetaldehyde seems to be a secondary alcohol but really it can react as a carbonyl
compound (it can be oxidized to acyl group), because the carbon atom between N+ and S is a
38
reactive carbon atom with acidic (dissociable) proton. During the decarboxylation of pyruvate the
molecule reacts as an acetaldehyde and the properties of the product is similar to a glucoside (its
hydroxyl group is a glycosidic hydroxyl). This kind of structure is called C-glycoside.
Acetaldehyde in free form can not be originated from the reaction of pyruvate and TPP. It
can be synthesized mostly from ethanol by oxidation followed by its oxidation to acetic acid in
the liver catalyzed by enzyme alcohol dehydrogenase. In contrast to acetic acid acetaldehyde is a
toxic molecule. The elevated acetaldehyde concentration in blood is responsible for the symptoms
of discomfort feeling after heavy drinking (hangover). It is a probable carcinogen. In the liver of
heavy drinkers a defect in the biosynthesis of alcohol dehydrogenase can be found causing
permanent drunkenness.
Thiamine is synthesized only in bacteria, fungi, and plants. The thiazole and pyrimidine
moieties are synthesized separately and then they are assembled to thiamine-phosphate. The exact
biosynthetic pathways can be slightly different in different organisms. The starting material of
pyrimidine moiety is a 5-aminoimidazole derivative that is an intermediate of purine biosynthesis.
There are three types of precursors of the thiazole moiety: an amino acid (glycine or tyrosine),
some sugar derivative and cysteine.
Insufficient intake in birds produces a characteristic polyneuritis. In mammals thiamine
deficiency results in a disease called beriberi affecting the peripheral nervous system
39
(polyneuritis) and/or the cardiovascular system, with fatal outcome without thiamine. In less
severe deficiency there are non-specific symptoms include tiredness, weight loss, irritability and
confusion.
Thiamine is found in a wide variety of foods at high concentrations. Yeast and pork are
the best sources, but cereal grains are rich in thiamine, as well. The whole grains contain more
thiamine than refined grains, as thiamine is found mostly in the inner layers of the grain and in the
germ (which are removed during the refining process). It is known that the rich people in ancient
Japan or China were more susceptible to beriberi than poor ones because they consumed husked
rice.
CH2NH2
CHO
CH OH
2
CH O– P
HO
CH OH
CH2O– P
HO
2
HO
Pantothenic acid
(vitamin B5) 2
The name of pantothenic acid means from everywhere in Greek (pantothen) because small
N
H3C in N
3C high
H3C
N acid are found
quantities of pantothenic
nearly every food,Hand
amounts are in wholepiridoxin
piridoxamin-foszfát
grain cereals, legumes,
eggs and meat. piridoxál-foszfát
Pantothenic acid is an ingredient
in some hair and skin
(B
-vitamin)
(PAM)
(PAL)
care products. Pantothenic
acid is one of the starting materials of coenzyme A (CoA) (this is the
6
only coenzyme that served
the original szállító
nomenclature
was vitaminja
similar to the nomenclature of
Az aminocsoportot
koenzim ésthat
prekurzor
vitamins)
NH2
N
P O P
O CH2
CH2
CH3
C CH3
O
C=O
NH
P
CH2
-alanin
OH
CH3
C CH3
CH–OH
C=O
NH
C=O
NH
C=O
NH
CH2
SH
Koenzim-A
H
2,4-dihidroxiO
3,3-dimetilvajsav
P
H
H
OH
CH2OH
CH2
CH2
ciszteamin
O
H
CH2
CH2
O CH2
CH2
H
H
CH–OH
P O P
O
H
N
N
O
H
N
N
N
N
O
NH2
N
CH3
CH2
C CH3
CH–OH
C=O
NH
CH2
CH2
S–C–CH3
CH2
O
CH3–CO–SKoA
acetil koenzim A
"aktív ecetsav"
COOH
pantoténsav
(régen B9-vitamin)
(újabban B5 vitamin)
A koenzim-A különbözô formái
Transfer coenzyme – acetyl group – coenzyme A
The acyl derivatives coenzyme A containing macroerg bond can transfer acyl group in the
biochemical processes. Acetyl-CoA is not only a transfer component for a C2 fragment but it is
40
the common metabolite during the oxidative degradation of different biomolecules entering to
citric acid cycle to produce CO2 and reduced coenzymes. During the regeneration (reoxidation) of
these reduced coenzymes in terminal oxidation (respiratory chain) energy can be produced by
forming macroerg bonds of ATP. CoA is also important in the biosynthesis of many important
compounds such as fatty acids, cholesterol, and acetylcholine.
Pantothenic acid deficiency is exceptionally rare and has not been thoroughly studied.
Symptoms of deficiency are similar to other vitamin B deficiencies. There is impaired energy
production, due to low CoA levels, which could cause symptoms of irritability, tiredness and
apathy. Acetylcholine takes play an important role in the function of nervous system (it is one of
the neurotransmitters), therefore neurological symptoms can also appear in deficiency of
pantothenic acid. In the case of low pantothenic acid concentration hypoglycemia or an increased
sensitivity to insulin also can be found. It can be in connection with the change in acylation
capacity.
As it was mentioned earlier small quantities of pantothenic acid are found in most foods.
The major food source of pantothenic acid is in meats, although the concentration found in food
animals' muscles is only about half that in humans' muscles. Whole grains are another good
source of the vitamin, but milling often removes much of the pantothenic acid, as it is found in
the outer layers of whole grains. Vegetables, such as broccoli and avocados, also have an
abundance of the acid.
The biosynthesis of -ketoisovaleric acid that is the starting material of pantothenic acid
The starting material of Co-A is pantothenic acid. Pantothenic acid is the amide between
pantoate (2,4-dihydroxy-3,3-dimethylbutyric acid) and -alanine. Pantoate (pantoic acid) is
synthesized from -ketoisovaleric acid. -Alanine is connected to pantoic acid by means of
energy of a macroerg bond of ATP. that is phosphorylated than a peptide bond with cysteine (with
the energy of a macroerg bond of ATP) is formed. Cysteine part of this molecule looses a
molecule of CO2 forming a cysteamine part (4’-phosphopantethein). This molecule reacts with
ATP followed by the phosphorylation of 3’-hydroxyl group of the ADP part of the molecule with
another ATP.
41
42
Transfer of other groups
For the transfer of phosphate group phosphorylating agents (NTP, especially ATP) are
used. The coenzyme of transfer of amino group is pyridoxal phosphate (PAL) synthesized from
pyridoxine (vitamin B6)
Pyridoxine (vitamin B6)
Pyridoxine is the starting material of the biosynthesis of pyridoxal phosphate. It is not
normally found in plants. This vitamin is made by certain bacteria. Some vegetarians may get
adequate pyridoxine simply from eating plants that have traces of soil (like potato skins). Most
people get their supply of this vitamin from either milk or meat products.
H3C
CH2O– P
HO
CH2OH
HO
CH2NH2
CHO
CH2OH
H3C
N
piridoxin
(B6-vitamin)
CH2O– P
HO
H3C
N
N
piridoxamin-foszfát
(PAM)
piridoxál-foszfát
(PAL)
Az aminocsoportot szállító koenzim és prekurzor vitaminja
Transfer coenzyme – amino group – PAL-PAM and its starting material pyridoxine
H2O
CH3 

C O
H
acetaldehid
CH3 CH
H2N
CH
+
N
R
AN
COOH
CH3 CH
a fenntiek szerint
C
R
R
-aminosav
H2O
COOH
H
CH3 CH N
C
N
C
COOH
H2O
CH3 CH2
N
ketimin
C
COOH
CH3CH2
R
H
R
H
COOH
COOH
H2O
NH2 +
etil-amin
O
C
R
-keto-karbonsav
Aldimin – ketimin tautomer átalakulás
Aldimine-ketimine
tautomerism illustrated
on acetaldehyde molecule
O–H
O 
H
H
 
H
C N
H +
phosphate
(PAL
C
C
genciobióz
C
C
O
C
genciobióz
Pyridoxal
or PLP) containing an N
aldehyde group is a prosthetic
group of
N
some enzymes of amino acid biochemistry. It takes part in all transamination reactions, and in
amigdalin it can transfer
benzaldehid
some decarboxylation
and deaminationbenzaldehid-ciánhidrin
reactions. In transamination reactions
(mandulaillat)
A keserûmandula szaganyaga
amino group
of amino acids by an aldimine-ketimine
tautomerism. This tautomerism is illustrated
on acetaldehyde instead of PAL. The name of amine containing coenzyme version is
pyridoxamine phosphate (PAM).
43
The pyridoxine deficiency can cause different problems in amino acid metabolism. Earlier
pellagra was attributed to pyridoxine deficiency. Later on it came to light that pellagra is caused
by niacin deficiency. In the case low L-tryptophane and pyridoxine level the biosynthesis of
niacin is not enough. There are biogenic amines playing different important roles in the nervous
system. Cholamine: H2N–CH2CH2–OH is formed from serine, and its methylated derivative is
choline: (CH3)3N–CH2CH2–OH. Acetylcholine is one of the neurotransmitters in nervous
system. Pyridoxine deficiency can cause low acetylcholine level.
Formation of biogenic amines
There is another important biogenic amine GABA formed from glutamic acid. Its official
name is 4-aminobutyric acid, earlier -aminobutyric acid. Its short name GABA is from the latter
name. GABA is the most important inhibitory neurotransmitter in the mammalian central nervous
system. It can moderate the sensitivity of neurons in the nervous system. Since GABA does not
penetrate the blood brain barrier, GABA is synthesized in the brain from glutamic acid by means
of PAL via a metabolic pathway called GABA shunt. Therefore it is supposed that the reason of
the familiar pyridoxine-dependent epilepsy of babies is in connection with pyridoxine deficiency.
H2N
CH
COOH
CO2
H2N
CH2
CH2
CH2
CH2
CH2
COOH
COOH
glutaminsav (Glu)
-amino-vajsav (GABA)
A GABA keletkezése a glutaminsavból
Formation of GABA from glutamic acid
It was mentioned earlier pyridoxine is not synthesized in plants. The starting materials of
pyridoxine derivatives are dihydroxyacetone phosphate from glycolysis and acetaldehyde then
glycerinaldehyde-3-phosphate. The nitrogen of pyridine is from a glutamine.
44
Prenatal vitamins – Foetus-saving vitamins
It was known earlier that there are important vitamins, especially folic acid that can
prevent some structural birth defects as neural tube defect, anencephaly and spina bifida. Dr.
Czeizel, a Hungarian professor suggested that a combination of three vitamins (folic acid, vitamin
B12 and pyridoxine) can give a general prevention for foetus (except genetic damages): not only
for problems mentioned above but against congenital abnormalities of urinary tract, mainly
obstructive defects, and cardiovascular malformations, mainly conotruncal defects, including
ventricular septal defect. In addition, there was a trend in the reduction of isolated limb
deficiencies. There is a special bread is in the trade in USA with foetus-saving vitamins for
pregnant women. Later on it came to light that this bread prevents different cardiovascular
diseases (e.g. reduces the number of heart attacks) in the adult people, especially in middle-aged
men, as well. Among others folic acid and vitamin B12 can help the permanent thymidine
biosynthesis by methylation of uridine; and the combination of these three vitamins can eliminate
the dangerous homocysteine concentration.
2. Secondary metabolites
Definition and classification of secondary metabolites
Secondary metabolism is the metabolism of different organic compounds in the living
organisms which are generally needed for their functioning. Unlike primary metabolites, the
absence of secondary metabolites does not result in immediate death, but sooner or later it can
cause more or less malfunction in the living organisms.
Secondary metabolites are synthesized from the different intermediates of biomolecules.
Some of them are often restricted to a narrow set of species, especially in plants. The metabolism
of secondary metabolites is not directly connected with the energy household of the living
organism. Therefore their enzymes of oxidation-reduction reactions can use directly oxygen.
These enzymes (oxygenases) often use other types of coenzymes e.g. L-ascorbic acid (vitamin C).
The name ‘secondary metabolite’ is a generic term used for more than 30,000 different substances
– most of them are plant secondary metabolites. In contrast to the primary metabolites secondary
metabolites do not have nutrient characteristics for human beings. They are usually found in very
45
small amounts but have an effect on humans. Each plant family, genus, and species produces a
characteristic mix of these chemicals, and they can sometimes be used as taxonomic characters in
classifying plants. Secondary metabolites are produced by microbes, plants, fungi and animals,
but not by all of them. Humans use some of these compounds as medicines, flavourings, or
recreational drugs.
Secondary metabolites can be classified on the basis of their structure, their solubility in
various solvents, the pathway by which they are synthesized (their starting materials) or their
different biological functions. A simple classification of plant secondary metabolites includes
three main groups: the terpenes (made from mevalonic acid, composed almost entirely of carbon
and hydrogen), phenolics (made from simple sugars, containing benzene rings, hydrogen, and
oxygen), and nitrogen-containing compounds (mostly alkaloids). The books about secondary
metabolites this classification of are generally based on the starting materials.
According to their starting materials different types can be distinguished: carbohydrates
(e.g. simple sugars), amino acids or their starting materials, acetyl coenzyme A or the
intermediates of the metabolism of fatty acids or other intermediates. When the starting materials
are one or more malonyl coenzyme A molecules, the name of secondary metabolites are ketides
(oligoketides or polyketides).
The most important types of secondary metabolites are coenzymes (according to
numerous scientist coenzymes and vitamins are closer to primary than secondary metabolism),
regulating agents (e.g. hormones), attracting agents (e.g. the sweet sucrose, the fruit esters as
scent agents etc.) and defensive (repelling) agents (e.g. alkaloids, toxins, antibiotics etc.).
Alkaloids
Alkaloids are a diverse group of low molecular weight, nitrogen-containing compounds
mostly derived from amino acids and found in about 20% of plant species. The most known
alkaloids are plant-derived compounds but they can be produced by a large variety of other
organisms (bacteria, fungi, animals), as well. They are part of a group of natural products
(secondary metabolites). Alkaloids are playing a defensive role (repelling agents) in the plant
against herbivores and pathogens. Due to their potent biological activity many of the
approximately 12 000 known alkaloids are used as pharmaceuticals, stimulants, narcotics and
poisons. Plant-derived alkaloids often have pharmacological effects and they are used as
medications, as recreational drugs. Examples are the local anesthetic and stimulant cocaine, the
stimulant caffeine, nicotine, the analgesic morphine, or the antimalarial drug quinine. Although
alkaloids act on a diversity of metabolic systems in humans and other animals, they almost
uniformly invoke a bitter taste.
The name ‘alkaloids’ is derived from the basic properties of some known derivatives. But
this group also includes some related compounds with neutral and even weakly acidic properties.
Also some synthetic compounds of similar structure are attributed to alkaloids. Beside carbon,
hydrogen and nitrogen, molecules of alkaloids may contain sulfur and rarely chlorine, bromine or
phosphorus.
The importance of alkaloids since the birth of human civilization is well illustrated by the
drug opium, which is obtained from opium poppy (Papaver somniferum) and contains the
analgesic morphine and numerous related alkaloids. Morphine is named after the Greek god
Morpheus, the creator of sleep and dreams. In the epic story the Odyssey, opium is used as an
ingredient in a wine-based drink called Nepenthes (Greek ne: not, penthos: sorrow) that was
46
consumed by soldiers before combat to forget the horrors of battle. Socrates was one of the
founders of Western philosophy in ancient Greece. His most important contribution to Western
was his dialectic method of inquiry. Because of political reasons he had to commit suicide by
hemlock containing coniine. The Roman Emperor Nero murdered his stepbrother Britannicus
with a mix of hemlock and opium. In most cultures, opium use was restricted to pain relief until
the seventeenth century when recreational use of the drug began in China. The Opium Wars were
fought between the British and Chinese to maintain free trade of the drug between the two
countries. Opium remains the only commercial source for morphine and codeine.
The boundary between alkaloids and other nitrogen-containing natural compounds is not
clear-cut. Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines and
antibiotics are usually not called alkaloids. Natural compounds containing nitrogen in the
exocyclic position (mescaline, serotonin, dopamine, etc.) are usually attributed to amines rather
than alkaloids. Some authors, however, consider alkaloids a special case of amines.
Compared with most other classes of natural compounds, alkaloids are characterized by a
great structural diversity and there is no uniform classification of alkaloids. Historically, first
classification methods combined alkaloids by the common natural source, e.g., a certain type of
plants. This classification was justified by the lack of knowledge about the chemical structure of
alkaloids and is now considered obsolete. More recent classifications are based on similarity of
the carbon skeleton
Influence of alkaloids on nerve cells
About nervous system
Alongside the other components of the autonomic nervous system, the sympathetic
nervous system aids in the control of most of the body's internal organs. The parasympathetic
system generally works to promote maintenance of the body at rest. Phrenic nerve contains motor,
sensory, and sympathetic nerve fibers. The neuron is the functional unit of the nervous system.
Humans have about 100 billion neurons in their brain alone. Nerve cells (neuron) interact with
other nerve cells at junctions called synapses. In the sympathetic nervous system the synapses
between the short first (preganglionic neurons) and the long second (postganglionic neurons)
neurons are called ganglions. The second synapses are between the second neurons and the
peripheral target tissues. In the parasympathetic nervous system the neurons lead directly to the
peripheral target tissues and the synapses are between the neurons and the target tissues.
The sympathetic nervous system
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The plasma membrane of neurons, like all other cells, has an unequal distribution of ions
and electrical charges between the two sides of the membrane. The outside of the membrane has a
positive charge, inside has a negative charge. This charge difference is a resting potential and is
measured in millivolts. Passage of ions across the cell membrane passes the electrical charge
along the cell. The voltage potential is -65mV (millivolts) of a cell at rest, it is called resting
potential. Resting potential results from differences between sodium and potassium positively
charged ions and negatively charged ions in the cytoplasm. Sodium ions are more concentrated
outside the membrane, while potassium ions are more concentrated inside the membrane. This
imbalance is maintained by the active transport of ions to reset the membrane known as the
sodium-potassium pump. The sodium-potassium pump maintains this unequal concentration by
actively transporting ions against their concentration gradients.
The sodium-potassium pump
The Na+/K+-ATPase helps maintain resting potential by an active transport. There are
several secondary membrane transport proteins, which import glucose, amino acids, and other
nutrients into the cell using of the sodium gradient by symport. Later on these sodium ions are
transported back to outside, to the intercellular region Na+/K+-ATPase by active transport. Inside
of the cell three of sodium ions bind to the active site of this enzyme followed by a
phosphorylation by ATP that causes a conformational change in the active site transporting
sodium ions and the phosphorylated part to outside (eversion). This altered conformation is
disadvantageous for sodium ions therefore they leave the enzyme followed by binding of two
potassium ions. The presence of potassium ions causes a dephosphorylation followed by a
conformational change in the active site again transporting potassium ions to inside (eversion
again). This original conformation cannot bind potassium ions. After the releasing potassium ions
the active site is ready for an active transport again.
There are similar pumps in the cell membrane. Ca2+-ATPase similarly can transport
calcium ions out of the cells, but in this case the site of phosphorylation remains inside of the cell.
Proton pump of the stomach works in the same way as Ca2+-ATPase does maintaining low pH
value inside.
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The proposed mechanism for sodium-potassium pump
Because of the connection a stimulating agent (e.g. the effect of adrenaline) to the receptor
the permeability of the membrane of the preganglionic neuron changes, this process is called
depolarization. On the effect of depolarization a transport of electron can be occurred in the
preganglionic neuron until the presynaptic membrane of ganglion. The transmission of the signal
though the synapse is by means of neurotransmitters. The neurotransmitter of the first synapse
(ganglion) in the sympathetic nervous system and of the only synapse in the parasympathetic
nervous system is acetylcholine; and the neurotransmitter of the second synapse in the
sympathetic system is noradrenaline (norepinephrine).
Depolarization the postsynaptic membrane by increasing the conductance of sodium and
potassium ions
The neurotransmitters are deliberated from their special storing places (vesicles) and
through the synapse they connect to the receptor of the postsynaptic membrane causing a
depolarization in the membrane of the second neuron in the sympathetic nervous system or of the
peripheral target tissues in the parasympathetic nervous system. The neurotransmitter of the
second synapse of between the first and the second neuron in the sympathetic nervous system is
noradrenaline. The place on the postsynaptic membrane where neurotransmitter is connected is
really the substrate binding site of the neurotransmitter on the receptor (cholinerg receptor for
acetylcholine and adrenerg receptor for noradrenaline) for its degradation (hydrolysis for
acetylcholine and oxidative deamination for noradrenaline). After degradation the residues of the
neurotransmitter go back into the postsynaptic membrane for regeneration. In the case of
receptors (active sites on the surface of membranes) the agents for activation are called agonists
and the inhibitors are called antagonists.
The first synapse - the function the active site of cholinesterase
The name of the substrate binding site of cholinesterase is anionic site because it can bind
the ammonium cation part of acetylcholine by ionic interactions. The connection of acetylcholine
starts depolarization. The name of the catalytic site of cholinesterase is esterase site. The
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hydrolyzing agent of the ester group is the hydroxyl group of a serine activated by a strong
hydrogen bond by histidine. After the hydrolysis choline leaves the anionic site that stops
depolarization. The acetylated serine in the esterase site is hydrolyzed by a water molecule.
The function of the active site of cholinesterase
After the return of choline and acetic acid to the presynaptic membrane the steps of the
regeneration are the activation of acetic acid to acetyl-CoA using ATP and coenzyme A followed
by the reaction between acetyl-CoA and chlorine then the last moment is the return of this
regenerated acetylcholine to vesicles.
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The biosynthesis and degradation of acetylcholine
The function of cholinesterase can be influenced in two steps: binding acetylcholine to the
anionic site (no depolarization) and the leaving the active site (permanent depolarization). The
anionic site can be inhibited by competitive inhibition of bioisostere molecules – e.g. alkaloids.
Permanents depolarization can be caused by the phosphorylation of serine in the catalytic site by
organic phosphate pesticides. Without ester hydrolysis acetylcholine can not leave the substrate
binding site, this is the reason of permanent depolarization.
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There are two different kinds of cholinerg receptors, they can be distinguished on the basis
of their sensitivity to alkaloids nicotine (nicotinic acetylcholine receptors) and muscarine
(muscarinic acetylcholine receptors). Nicotinic receptors are responsible for the initial fast
depolarization of neurons. However, the subsequent hyperpolarization and slow depolarization of
the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types
M2 and M1 respectively. M1-type muscarinic acetylcholine receptors play a role in cognitive
processing. In Alzheimer disease amyloid formation (insoluble fibrous protein aggregates sharing
specific structural traits) may decrease the ability of these receptors to transmit signals leading to
decrease cholinergic activity. M1-type muscarinic acetylcholine receptors can play a role in
schizophrenia that is a mental disorder with hallucination and paranoid or bizarre delusions.
There are important M3 muscarinic receptor agonists those are used medically for a long
time. Arecoline is an alkaloid containing pyridine ring that is present in Betel nut (Areca nut)
(often wrapped in betel leaves are chewed in India). Pilocarpine containing imidazole ring is used
in the treatment of chronic glaucoma. Glaucoma is a disease in which the optic nerve is damaged,
leading to progressive, irreversible loss of vision. It is often, but not always, associated with
increased pressure of the fluid in the eye.
Acetylcholine is the natural agonist of both kinds of receptors. It has two types of effects.
The first type is termed muscarinic, which is the parasympathetic effect on the secretory exocrine
glands, and on smooth and cardiac muscles through their corresponding receptors. The other type
of its effect is termed nicotinic, which is on the skeletal (voluntary) muscles; it is not considered
to be part of the peripheral autonomic nervous system.
Nicotine containing pyridine ring is the most important alkaloid of tobacco plant. Tobacco
(Nicotiana tabacum), a native plant of the Americas and was in widespread use when Columbus
arrived in the New World in 1492. Tobacco was sniffed, chewed, eaten, drunk, applied topically
to kill parasites and used in eye drops and enemas. The act of smoking tobacco appears to have
evolved from snuffing and is currently the most common means of administration. Tobacco was
used ceremonially, medicinally and for social activities. Ironically, one of the first medicinal uses
of tobacco was based on its purported anticancer properties.
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Tobacco contains several structurally similar other pyridine alkaloids, as well. Nicotine
acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and
one CNS (central nervous system) nicotinic receptor. In small concentrations, nicotine increases
the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters
through less direct mechanisms. Nicotine appears to enhance concentration and memory due to
the increase of acetylcholine. Anxiety is reduced, the positive effects of dopamine on the brain
(cognition, motivation) are extended and the sensitivity in brain reward systems is increased. The
pyridine ring containing alkaloids are mostly synthesized from nicotinic acid.
Nicotine, muscarine, arecoline and pilocarpine
Smoking tobacco is a major cause of heart disease, stroke, peripheral vascular disease,
chronic obstructive pulmonary disease, lung and other cancers, and various gastrointestinal
disorders. Smoking can cause many other health problems including osteoporosis, impaired
fertility, inflammatory bowel disease, diabetes and hypertension. Tobacco smoke contains a
multitude of chemicals including polycyclic aromatic hydrocarbons; thus, nicotine is not solely
responsible for these disorders. However, nicotine is one of the most biologically active
chemicals in nature, binding to several different receptors and activating a number of key signal
transduction pathways. Many of the physiological effects of nicotine, including addiction, are
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exerted by its action on nicotinic acetylcholine receptors. Nicotine modulates the
phosphatidylinositol pathway and increases intracellular calcium levels, which are both universal
signalling components in physiological processes. The carcinogen effect of smoking is in
connection with tar products of burning, but nicotine can promote the oxidative damage of
reactive oxygen species.
Biosynthesis of nicotine
Coniine containing saturated pyridine ring (pyperidine ring) is the most important alkaloid
of hemlock (Conium maculatum) that is native to Europe and western Asia. It contains seven
structurally similar other piperidine alkaloids, as well. Including these piperidine alkaloids are
synthesized from eight acetate units therefore they are polyketides. Coniine is a typical antagonist
of nicotinic acetylcholine receptors by competitive inhibition. It induces a neuromuscular
blockage later on paralyses the respiratory muscles.
Coniine
Muscarine containing tetrahydrofurane ring is an alkaloid of certain mushrooms.
Muscarine acts as a selective agonist of the neurotransmitter acetylcholine on smooth muscles of
the gastrointestinal tract, eye exocrine glands, and heart. It causes a strong activation of the
peripheral parasympathetic nervous system that may end in convulsions and death. Muscarine
poisoning is characterized by increased sweating and lacrimation within 15 to 30 minutes after
ingestion of the mushroom. Death is rare, but may result from cardiac or respiratory failure in
severe cases.
The starting material of alkaloids containing pyridine ring is nicotinic acid that is
synthesized from L-tryptophane. Pyrrolidine part of nicotine is synthesized from N-methyl-’-
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pyrrolinium cation formed from L-ornithine. This cation is one of the starting materials of
atropine that is a competitive antagonist of acetylcholine for the muscarinic acetylcholine
receptors. Atropine is a racemic mixture of D- and L-hyoscyamine, with most of its physiological
effects due to L-hyoscyamine. Its pharmacological effects are due to binding to muscarinic
acetylcholine receptors. It is an antimuscarinic agent. Atropine effects on the vagus nerve (in
Hungarian bolygóideg) of the parasympathetic nervous system on the heart. This effect decreases
heart rate. As acetylcholine is the hormone of the waves of rhythmic (peristaltic) contraction
move along the gut, atropine can decrease of the absorption of different poisons. Atropine is also
an antagonist of the inhibitors of cholinesterase enzyme. Atropine can cause ventricular
fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of
balance, dilated pupils, photophobia, dry mouth and potentially extreme confusion, dissociative
hallucinations and excitation especially amongst the elderly people. Atropine is an alkaloid with a
tropan skeleton from deadly nightshade (Atropa belladonna) and other plants of the family
Solanaceae.
Scopolamine is an analogue of atropine containing an oxirane ring. It is less toxic as
atropine is. It can be used as a depressant of the central nervous system, and was formerly used as
a bedtime sedative. It can be used also against both major depressive disorder and depression due
to bipolar disorder. Earlier it was supposed to be a truth serum.
In spite of their structure (it is a tropane alkaloid) cocaine can be in connection with
noradrenaline, as well. Cocaine can be obtained from the leaves of the coca plant. It is a stimulant
of the central nervous system, an appetite suppressant, and a local anesthetic. Specifically, it is a
serotonin-noradrenaline-dopamine reuptake inhibitor, which mediates functionality of these
neurotransmitters as an exogenous catecholamine transporter ligand.
Atropine (DL-hyoscyamine), scopolamine (L-hyoscine) and cocaine
Physostigmine (also known as eserine from éséré, West African name for the Calabar
bean) is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor alkaloid of the
Calabar bean. It indirectly stimulates both nicotinic and muscarinic receptors. Its mechanism is to
prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of
acetylcholine. This inhibition enhances the effect of acetylcholine, therefore it can be useful for
the treatment of cholinergic disorders e.g. to improve the memory of Alzheimer’s patients due to
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its potent anticholinesterase activity. Earlier West Africa native population was used
physostigmine as an ordeal. The innocent persons were killed by the treatment. The guilty ones
survived the treatment, therefore they had to be killed. This was similar to ordeal by water in
Europe in the Middle Ages. Neostigmine is a synthetic drug with the same action.
The second synapse – neurotransmitter is noradrenaline
The biosynthesis and degradation of noradrenaline
The second synapses are between the second neurons and the peripheral target tissues.
The starting material of noradrenaline (norepinephrine) is L-tyrosine. Similarly to other
secondary metabolites oxygenase (hydroxylase) enzymes using molecular oxygen play role in its
biosynthesis. The product of the first step of the synthesis (catalyzed by tyrosine hydroxylase) is
L-3,4-dihydroxyphenylalanine. Its short name L-DOPA (levodopa) is from its earlier name
(dioxyphenylalanine). Dopa is the starting material of melanin in enzymatic browning of fruits
and other parts in plants. Dopa, dopamine and noradrenaline are catecholamines containing both
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catechol (ortho-dihydroxybenzene) phenylethylamine structures. Catecholamines are
sympathomimetic ‘fight-or-flight’ (fight or escape) hormones released by the adrenal glands in
response to stress.
The biosynthesis of papaverine and morphine
Noradrenaline is a catecholamine with multiple roles including as a hormone and a
neurotransmitter. It increases blood pressure by its activation effect on adrenergic receptors. It can
directly increase heart rate, trigger the release of glucose from energy stores, and increase blood
flow to skeletal muscle. The degradation products of noradrenaline are different. One of the most
important product is 3,4-dihydroxymandelic acid (an oxidised product of 3,4-dihydroxyphenyl
glycolaldehyde that is the first oxidised product of the oxidative degradation of noradrenaline
catalyzed by monoamine oxidase MAO).
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Papaverine
Many benzylisoquinoline alkaloids are used as pharmaceuticals due to their potent
pharmacological activity, which is often an indication of the biological function of the
approximately 2500 known members of this group. Their effectiveness suggests that these
alkaloids function as herbivore deterrents (protection from infections by micro-organisms).
Benzylisoquinoline alkaloids occur mainly in basal angiosperms including the Ranunculaceae,
Papaveraceae, Berberidaceae, Fumariaceae,Menispermaceae and Magnoliaceae. The structure of
these alkaloids always contains phenylethyl structure that suggests an agonist effect on the
adrenerg receptors. These receptors are called opiate receptors.
A morphine, a codeine and heroin
Benzylisoquinoline alkaloid biosynthesis begins with decarboxylations, orthohydroxylations and deaminations that convert tyrosine to both dopamine and 4hydroxyphenylacetaldehyde. The reaction between these two products results in the starting
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material of both papaverine (that is its polymethylated derivative) and morphine (after a special
kind of cyclization). The methylation of one of hydroxyl groups of morphine results in codeine.
Heroin is a diacetylated, synthetic derivative of morphine. These are opium alkaloids obtained
from opium poppy (Papaver somniferum).
Papaverine is used primarily in the treatment of different kinds of spasm. Morphine is an
analgesic and recreational drug. Because the possibility of drug-addiction its use is allowed only
for cancer patients with terrible pains under control. Diacetylmorphine (heroin) is used as both an
analgesic and a recreational drug. Frequent and regular administration is associated with tolerance
and physical dependence, which can cause addiction. Internationally, diacetylmorphine is
controlled under Schedules I and IV of the Single Convention on Narcotic Drugs. It is illegal to
manufacture, possess, or sell diacetylmorphine without in almost all of countries. Drug-addition
leads not only to degradation in the physical status of a person but in mental and moral status, as
well.
Lisergic acid and its diethylamide (LSD)
Lysergic acid, also known as D-lysergic acid and (+)-lysergic acid, is a precursor for a
wide range of ergoline alkaloids that are produced by the ergot fungus (Claviceps purpurea).
There are ergoline alkaloids (e.g. ergotamine) those can contract blood vessels causing serious
pains and necroses in both limbs and internal parts. This fungus can grow easily on rye in the case
of cold and rainy weather. Ergoline alkaloids getting into flour and bread caused terrible illness
and death. In the Middle ages it was thought that it is an epidemic caused by sexual sins. Amides
of lysergic acid (lysergamides) are widely used as pharmaceuticals and as psychedelic drugs
(increase of consciousness). Lysergic acid is usually produced by hydrolysis of lysergamides.
Lysergic acid diethylamide, abbreviated (LSD) a semisynthetic psychedelic drug of the ergoline
family. LSD is non-addictive and well known for its psychological effects which can include
altered thinking processes, closed and open eye visuals, an altered sense of time and spiritual
experiences. It is used mainly as a recreational drug and as an agent in psychedelic therapy. It is
dangerous because it can cause a long lasting effect by modifying of the receptor. LSD can
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replace serotonin in the central nervous system. Serotonin can regulate sleep, mood and it has
other important functions including cognitive function (e.g. memory and learning).
Serotonin
Literature
1. Bender, D.A.: Nutritional biochemistry of the vitamins. Cambridge University Press
Cambridge New York Port Chester Melbourne Sydney 1992.
2. Luckner, M.: Secondary metabolism in microorganisms, plants and animals. Springer-Verlag
Berlin Heigelberg New York London Paris Tokyo Hong Kong 1990.
3. Stryer, L.: Biochemistry (3rd Edition) W.H. Freeman & Company New York 1988.
4. Crozier, A., N. Clifford, M.N., Ashihara, H.: Plant Secondary Metabolites. Blackwell
Publishing Oxford 2006.
Topics in Nutritional biochemistry of the vitamins and secondary metabolites
Assay questions – Two of these topics in short essay form in the exam.
Exam 1-10
1. Definition and types of essential materials. Definition and types of secondary metabolites.
Classification of vitamins – the role of solubility.
2. Precursors of coenzymes of oxydoreductases : niacin, riboflavin.
3. Antioxidant vitamins (ascorbic acid and tocopherols) and lipid peroxidation.
4. Precursors of coenzymes of transferases – C1 transfer: biotin, folic acid.
5. Precursors of coenzymes of transferases – C1 transfer: biotin, cyanocobalamin.
6. Precursors of coenzymes of transferases – C2 transfer: thiamin, pantothenic acid.
7. Precursors of coenzymes of transferases – transfer of other groups: pyridoxine and its
connection with foetus-saving vitamins.
8. Vitamin lipids (retinol and -carotene, cholecalciferol and its vitamers).
9. Definition and types of secondary metabolites. Alkaloids and the nervous system. Cholinerg
systems.
10. Definition and types of secondary metabolites. Alkaloids and the nervous system. Adrenerg
systems.
1+9, 4+10, 2+5, 3+7, 6+8.
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