Download Vitamins and Coenzymes

TUMS
Dr. Azin Nowrouzi, PhD
Tehran University of Medical Sciences
1
9. FOLIC ACID (folacin)
• Folacin includes several derivatives of folic acid
(monopteroylglutamic acid).
• Folic acid is obtained primarily from yeasts and leafy vegetables as
well as animal liver. Animals cannot synthesize PABA nor attach
glutamate residues to pteroic acid, thus, requiring folate intake in the
diet.
“Microorganisms
Only can
synthesize Folacin”
Sulphonamides
and antibiotics
block PABA
incorporation
by competitive
inhibition
2
Structure
Folic acid exists in a polyglutamate form. Intestinal mucosal cells
remove some of the glutamate residues through the action of the
lysosomal enzyme, conjugase.
3
Active functional form is:
Tetrahydrafolic acid
(THF).
Humans and microorganisms:
Folic acid is reduced within cells
(principally in the liver where it is
stored) to tetrahydrofolate (THF or
H4folate) through the action of
folate reductase [or
dihydrofolate reductase (DHFR) ]
which is an NADPH-requiring
enzyme.
4
Active center (N5 and N10)
5
• Active center of tetrahydrofolate (THF). The N5 position is the site of
attachment of methyl and formimino groups, the N10 the site for
attachment of formyl group and that both N5 and N10 bridge the
methylene and methenyl groups.
6
Folate conversions
Carrier of one-carbon (e.g. methyl) groups
The one-carbon units are added to, or removed from, metabolites such as:
•
histidine
•
serine
•
methionine
•
purines.
7
Functions
1. Role of N5,N10-methylene-THF in dTMP
synthesis is the most metabolically
significant function for this vitamin.
2. Vitamin B12 and N5-methyl-THF in the
conversion of homocysteine to methionine
is important in helping cells to regenerate
needed THF.
8
Participation of H4folate in dTMP synthesis
______Deoxyuridine______________
________Deoxythymidine
____Monophosphate (dUMP)_______________Monophosphate (dTMP)_______
9
Deficiency symptoms
Deficiency is rare due to the adequate presence of folate in food.
Deficiency can occur when there is:
1. Poor dietary habits as those of chronic alcoholics.
2. Impaired absorption or metabolism
• Certain drugs such as anticonvulsants and oral contraceptives and
methotrxate can impair the absorption of folate.
3. An increased demand for the vitamin.
• Pregnancy
• Folate will nearly double by the third trimester of pregnancy.
• Identical to those for vitamin B12 deficiency:
• Effect of folate deficiency on cellular processes
is upon DNA synthesis.
– Impairment in dTMP synthesis and purine synthesis
– Cell cycle arrest in S-phase of rapidly proliferating cells, especially
hematopoietic cells.
• The result is megaloblastic leukemia as for vitamin B12 deficiency.
– The inability to synthesize DNA during erythrocyte maturation leads to
abnormally large erythrocytes termed macrocytic anemia.
• Deficiency during pregnancy can cause neural tube defects such as
spina bifidia.
10
VITAMIN B12 (cobalamin)
•
Vitamin B12, is also called cobalamin,
cyanocobalamin and hydroxycobalamin.
•
It is built from :
1. A nucleotide and
2. A complex tetrapyrrol ring structure
(corrin ring)
3. A cobalt ion in the center.
4. A R- group
•
•
•
When R is cyanide (CN), vitamin B12
takes the form of cyanocobalamin.
In hydroxycobalamin, R equals the
hydroxyl group (-OH).
In the coenzyme forms of vitamin B12,
–
–
•
R equals an adenosyl group in
adenosylcobalamin.
R equals a methyl (-CH3) group in
methylcobalamin.
Vitamin B12 is synthesized exclusively by
microorganisms (bacteria, fungi and algae)
and not by animals and is found in the liver
of animals bound to protein as
methycobalamin or 5'deoxyadenosylcobalamin.
11
• Known as the "red" vitamin because it exists as
a dark red crystalline compound, Vitamin B12 is
unique in that it is the only vitamin to contain
cobalt (Co3+) metal ion, which, gives it the red
color.
• The vitamin must be hydrolyzed from protein in
order to be active.
• Intrinsic factor, a protein secreted by parietal
cells of the stomach, carries it to the ileum
where it is absorbed.
• It is transported to the liver and other tissues in
the blood bound to transcobalamin II.
• It is stored in the liver attached to
transcobalamin I.
– It is released into the cell as
Hydroxocobalamin (see the next slide)
Dorothy Crowfoot Hodgkin
(1910-1994)
• In the cytosol it is converted to
methylcobalamin.
• Or it can enter mitochondria and be converted
to 5’-deoxyadenosyl cobalamin.
Dr. Stadtman in her lab
12
In the cytosol
In mitochondria
13
Functions
•
Only two reactions in the body require vitamin B12 as a
cofactor:
1. During the catabolism of fatty acids with an odd number of
carbon atoms and the amino acids valine, isoleucine and
threonine the resultant propionyl-CoA is converted to
succinyl-CoA for oxidation in the TCA cycle.
– methylmalonyl-CoA mutase, requires vitamin B12 as a cofactor in
the conversion of methylmalonyl-CoA to succinyl-CoA.
– 5'-deoxyadenosine derivative of cobalamin is required for this
reaction
2. The second reaction catalyzed by methionine synthase
converts homocysteine to methionine
– This reaction results in the transfer of the methyl group from N5methyltetrahydrofolate to hydroxycobalamin generating
tetrahydrofolate and methylcobalamin during the process of the
conversion.
14
Methionine and Folate cycles are interrelated
Methionine cycle
Folate cycle
Methionine
THF
CH2-THF
SAM
MS
Methyl
acceptor
methyl
transferases
B12
CH3-THF
Methyl
CH3- acceptor
Homocysteine
SAH
CBS
B6
cystathionine
Transulfuration
pathway
B6
cysteine
15
Deficiency symptoms
• Pernicious anemia in humans (inability to absorb B12
because of lack of gastric intrinsic factor).
• Neurological disorders due to progressive demyelination
of nerve cells.
– This results from increase in methylmalonyl-CoA.
– Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in
fatty acid biosynthesis.
– Can substitute malonyl-CoA in any fatty acid biosynthesis and
create branched-chain fatty acid altering the architecture of
normal membrane structure of nerve cells.
• Sources
– Synthesized only by microorganisms, so traces only are present
in plants; liver is a rich source.
– B12 is found in organ and muscle meats, fish, shellfish, dairy
products, eggs and in fortified foods like breakfast cereals.
16
Vitamin C (Chemical nature)
• It is derived from glucose via uronic acid pathway. Enzyme
L-gluconolactone oxidase is responsible for conversion of
gluconolactone to ascorbic acid.
• This enzyme is absent in primates, including humans, some bats….
• The active form is ascorbic acid itself.
17
VITAMIN C
• Vitamin C is L-ascorbic acid, which is a colorless,
crystalline acid with strong reducing properties.
• Functions
• Vitamin C has antioxidant properties similar to those of
vitamin E,
– Protects cells from free radicals.
– Protects iron from oxidative damage, thus enhancing iron (Fe2+)
absorption in the gut.
• The main function is as a reducing agent.
– It has the potential to reduce cytochrome a and c of the
respiratory chain and molecular oxygen and nitrates.
• It is required for various hydroxylation reactions e.g.
proline to hydroxypoline for collagen synthesis (see next
slide).
18
Hydroxylation of proline and lysine residues in
collagen
• Vitamin C is required for the maintenance
of normal connective tissue as well as for
wound healing because synthesis of
connective tissue is the first event in
wound tissue remodeling.
19
Other activities
• Several other metabolic reactions require
vitamin C as a cofactor:
– The catabolism of tyrosine and the synthesis
of epinephrine from tyrosine and the synthesis
of the bile acids.
– It is also believed that vitamin C is involved in
the process of steroidogenesis.
• The adrenal cortex contains high levels of
vitamin C which are depleted upon
adrenocorticotropic hormone (ACTH)
stimulation of the gland.
20
Roles in the body
Sources
• Citrus fruits and green leafy vegetables
• Vitamin C is readily absorbed and so the primary cause of vitamin C
deficiency is poor diet and/or an increased requirement.
Deficiency symptoms
1. Scurvy
–
–
–
–
–
–
Bleeding gums
Small red spots on skin
Rough skin
Wounds fail to heal
Weak bones and teeth
Anemia and infections
2. Stress (e.g., infections, smoking)
– Mechanism unknown, but vitamin C requirements increase during stress
3. Common cold?
4. Disease prevention?
– Cancer, heart disease
21
Periodontal disease
22
Vitamin B-complex
Vitamin Chemical name
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
Thiamine
Riboflavin
Nicotinamide (niacin)
Adenine (no longer considered a vitamin)
Pantothenic acid
Pyridoxine
Biotin
Inositol
Folacin (folic acid)
p-aminobenzoic acid (PABA) / H1
L-carnitine / b-hydroxy-g-trimethylammonium butyrate
(or choline)
Cyanocobalamin
23
8. Inositol (Vitamin Bh)
• Inositol is part of the vitamin B-complex.
• Since it is not essential in the human diet, it cannot be
considered a vitamin.
• Inositol is naturally present in foods high in fiber (wheat,
legumes, bran, etc).
• It is required for:
– For proper formation of cell membranes.
– For formation of lecithin
– It is not a vitamin per se, but it works synergistically with
many vitamins and nutrients.
• functions closely with a B complex vitamins, Choline, folacin,
Vitamins B-6 and B-12.
– Inositol is necessary for proper function of nerves, brain, and
muscles in the body.
– This nutrient is also often used to counter depression;
indeed, serotonin needs inositol for proper functioning.
– Exists in all human cells, where it plays an important role in
cell proliferation and differentiation.
• Low levels of this nutrient may result in depression and
some research has shown that increased levels of Inositol
appear to be a promising treatment for depression.
24
10. P-amino benzoic acid (Bx)
• A substance required for the synthesis of folic acid by
many organisms.
• PABA is an essential nutrient for some bacteria and is
sometimes called Vitamin BX.
• Para-aminobenzoic acid is included in the B-vitamin
complex, although it is not an essential nutrient for
humans and it varies in its activity from other B vitamins.
• Although humans lack the ability to synthesize folate
from PABA, it is sometimes marketed as an essential
nutrient under the premise that it can stimulate intestinal
bacteria.
• It also absorbs ultraviolet light and is used as
aminobenzoic acid, as a topical sunscreen. Abbreviated
PAB or PABA.
• The potassium salt is used as drug against fibrotic skin
disorders.
25
Structure
Folic acid
PABA (vitamin Bx)
26
11. L-CARNITINE (B11)
• L-carnitine
– Is made in the body from the amino acids
lysine and methionine,
– Is needed to release energy from fat.
– It transports fatty acids into mitochondria, the
powerhouses of cells.
– In infancy, and in situations of high energy
needs, such as pregnancy and breastfeeding, the need for L-carnitine can exceed
production by the body.
• Therefore, L-carnitine is considered a
"conditionally essential" nutrient.
27
L-carnitine
• L-carnitine’s actions appear to be particularly
important in the heart.
• As an example, patients with diabetes and high
blood pressure were given 4 grams of Lcarnitine per day in a preliminary study.
• After 45 weeks, irregular heartbeat and
abnormal heart functioning decreased
significantly compared with nonsupplemented
patients.
28
Sources of L-carnitine
• Dairy and red meat contain the greatest
amounts of carnitine. Therefore, people who
have a limited intake of meat and dairy products
tend to have lower L-carnitine intakes.
• Carnitine deficiencies are rare, even in strict
vegetarians, because the body produces
carnitine relatively easily.
• Rare genetic diseases can cause a carnitine
deficiency.
• Also, deficiencies are occasionally associated
with other diseases, such as diabetes and
cirrhosis.
• Most people do not need carnitine supplements.
For therapeutic use, typical amounts are 1–3
grams per day.
29
30
Vitamin classification
Name(Letter)
RDI
Retinol (A)
5000 IU
Calciferol (D)
400 IU
Tocopherol (E)
30 IU
Phylloquinone (K) 70 g
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Fat-soluble Vitamins
• Absorbed with dietary fat in small intestine
• 40-90% absorption efficiency
• Absorption typically regulated by need
– need absorption
• Transported away from small intestine in
chylomicra via blood and lymph (depending on
size)
• They are not easily excreted through urine.
• Substantial amounts are stored in liver and fat
tissue.
• Therefore, toxicity is possible.
32
Vitamin A
Compounds with 20-carbon structure.
Contain a methyl substituted cyclohexenyl ring (-ionone ring),
and an isoprenoid side chain with either a hydroxyl group, and aldehyde
group, a carboxylic acid group, or an ester group (retinyl ester) at the
terminal C15.
All-trans-retinal
Retinol
11-cis-retinal
Retinoic Acid
Can’t be reduced to retinol or retinal in the body.33
Vitamin A
1.
Active vitamin A- Preformed vitamin A can be obtained
either directly from foods that are substantial in vitamin
A (beef liver, fish liver oils, egg yolks and butter)
•
•
2.
The active form of vitamin is retinol, an alcohol which can be
converted to other forms (e.g. vitamin A esters) for storage in liver
and tissues.
much the body's vitamin A is stored in the liver as retinyl palmitate
Provitamin A- provitamins, substances that are
transformed into vitamins in the body
•
•
•
•
•
Beta-carotene is the most abundant and widespread provitamin A.
Beta-carotene comes from a group of compounds called the
"carotenoids (C40 polyisoprenoids).
One need to eat approximately six times as much beta-carotene
to get the same amount of vitamin A as in retinol.
Dark-green leafy vegetables (spinach) and yellow-orange
fruits (apricots and mango) and vegetables (carrots, yellow
squash and sweet potatoes) are high in beta-carotene and other
carotenoids (-carotene, -cryptoxathin, etc.)
Carotenoids are not toxic even at high doses for long times.
34
Vitamin A: Absorption and transport
-
-
-
-
Micelle formation
Inside mucosal cell -carotene is cleaved
in the lumen of the intestine by carotene dioxygenase to yield retinal.
Retinal is reduced to retinol by retinal
reductase, an NADPH requiring enzyme
within the intestines.
Retinol is esterified to palmitic acid and
delivered to the liver with chylomicrons
via lymphatic system.
- Carotenoids which escape intestinal
conversion to retinol can be stored in
adipose tissue.
- Species in which this occurs include
humans, horses and cattle, which
have yellow-pigmented body fat when
carotenoid intake is high.
Vitamin A absorption efficiency 70-90%;
carotenoids 9-22%.
35
Vitamin A: Biological functions
•
Role in vision. Vitamin A (retinal) is an essential precursor for formation of the
visual pigment, rhodopsin, in the retina of the eye. Retinal plays an
important role in vision, especially night vision. Lowers cataract incidence.
•
Role in growth. Helps regulate cell development, cell differentiation and cell
division.
•
Role in Bone and teeth formation. Promotes the proper growth of bones and
teeth. Bone cells (osteoblasts and osteoclasts) depend on vitamin A for their
normal functioning.
– Is important in the formation and maintenance of healthy hair, skin and
mucous membranes.
•
Role in reproduction. Vitamin A holds an important place in sexual
reproduction. Adequate levels of vitamin A are needed for normal sperm
production. The female reproductive cycle requires sufficient amounts of
vitamin A.
•
Boosts the body's immune system helping to increase body resistance to
infectious diseases.
36
Role of Vitamin A in Vision
(Wald’s visual cycle)
1. When the rhodopsin is exposed to light it is bleached releasing the
11-cis-retinal from opsin.
2. Isomerization of the cis-isomer of retinal to all-trans-retinal, causes
conformational changes in rhodopsin, hyperpolarization of the retinal
rod cell, and extremely rapid transmission of electrical activity to the
brain via the optic nerve
3. Trans-retinal is isomerized to cis-retinal in the dark, which
associates with opsin to regenerate rhodopsin.
All trans retinol
= main circulating
form of Vit A
37
Visual Pigment
Vitamin A: Biological functions
(Cell growth and differentiation)
• Regulation of gene expression by retinoic acid, the acid
form of vitamin A
• Retinoic acid is formed within the target cell from retinol
transported in the bloodstream.
• Retinoic acid, combined with protein receptor, acts as
transcription regulator by binding to specific sequences
of DNA in the nucleus
• Affected cells include epithelium of numerous tissues,
including skin and gut, and bone, ovary and testis.
• Retinoic acid is an especially important regulator of
embryonic cell differentiation.
38
Vitamin A: Deficiency symptoms
1. Night blindness" - lessened ability to see in dim light.
2. Increased susceptibility to infection and cancer and anemia
equivalent to iron deficient.
3. Prolonged lack of vitamin A
(keratinization of the cornea, a condition known as xerophthalmia).
4. Abnormal bone development in fetal and neonatal life.
5. Various congenital defects.
Retinol and its precursors are used as dietary supplements to prevent
the above symptoms.
Retinoic acid is used in dermatology to cure acne and psoriasis:
1. Mild acne (Darier’s disease) and aging
Topical application of tretinoin (all-trans retinoic acid), along with
benzoyl peroxide and antibiotics.
2. severe recalcitrant cystic acne
Oral consumption of isotretinoin (13-cis retinoic acid). This drug is
teratogenic. Should not be prescribed during pregnancy. It may lead to
hyperlipidemia and increased LDL/HDL ratio (increased chance of
heart disease) in long term.
39
Vitamin A: Toxicity
•
Hypervitaminosis A in humans
– Symptoms include dry, pruritic skin with excessive itching and increase in
intracranial pressure.
– is becoming an increasing problem in Western countries because of selfmedication and overprescription.
– has occurred through eating polar bear or seal liver by polar explorers.
• Eat polar bear liver sparingly, 30 grams contain 450,000 IU of retinol!
Continued ingestion causes peeling of the skin from head to foot.
• It is possible that some early Arctic explorers died from eating their sled
dogs in an attempt to survive.
40
41
Vitamin D
• Vitamin D is a family of fat-soluble
sterol compounds:
•
•
•
•
•
Vitamin D1 (lamisterol)
Vitamin D2 (ergocalciferol)
Vitamin D3 (cholecalciferol)
Vitamin D4 (dihydroergocalciferol)
Vitamin D5 (7-dehydrositosterol)
42
Vitamin D: Types and Sources
• For humans, the two most important forms of
vitamin D are:
– vitamin D2
– vitamin D3.
• Vitamin D2 (ergocalciferol) is derived from
plants and irradiated yeast and fungi.
• Vitamin D3 is synthesized in the body when
skin is exposed to sunlight
– Cholesterol + sunshine = Vitamin D3
– “sunshine vitamin” – UV-B rays (5-10 minutes arms
and legs, mid-day sun).
• Vitamin D3 can be obtained from foods like
milk, fortified cereals, tuna, salmon and fish
oils.
43
Sunlight
Vitamin D2
(Ergocalciferol)
Ergosterol
(in plants)
Diet
Sunlight
7-Dehydrocholesterol
Vitamin D3
Cholecalciferol)
44
Activation of Vitamin D
• Vitamin D2 and vitamin D3 are
biologically inactive but can
have equal biological activity:
• Both can be converted first to
calcifediol in the liver and then
to calcitriol, also known as
1,25-dihydroxycholecalciferol,
in the kidneys.
• Calcitriol, which is the most
active form of vitamin D3, is
then transported via a carrier
protein to the various sites in
the body where it is needed.
Calcitriol is also called
1,25-dihydroxy vitamin D3,
or (1,25-(OH)2D3.
45
1,25-dihydroxyvitamin D3
Conversion of 25-(OH)D3 to its
biologically active form, calcitriol,
occurs through the activity of a
specific D3-1-hydroxylase present
in the proximal convoluted tubules
of the kidneys, and in bone and
placenta. Cytochrome P450, O2
and NADPH are needed.
25-hydroxyvitamin D3
In the liver cholecalciferol is
hydroxylated at the 25 position
by a specific D3-25-hydroxylase
generating 25-hydroxy-D3 [25(OH)D3] which is the major
circulating form of vitamin D.
46
Functions of vitamin D
• Vitamin D regulates the calcium and phosphorus
levels in the blood by promoting their absorption
from food in the intestines, and by promoting reabsorption of calcium in the kidneys.
• It promotes bone formation and mineralization and
is essential in the development of an intact and
strong skeleton.
• It inhibits parathyroid hormone secretion from the
parathyroid gland.
• Vitamin D affects the immune system by promoting
immunosupression, phagocytosis, and anti-tumor
activity.
47
Vitamin D:
Hormone for Calcium and Phosphate regulation
•
•
Nerves and muscles must function properly; calcium is
vital for nerve cell transmissions and muscle fiber
contractions.
Calcitriol functions in concert with parathyroid hormone
(PTH) and calcitonin to regulate serum calcium and
phosphorous levels by:
1.
2.
3.
Increasing dietary calcium absorption from the small intestine.
Decreasing the urinary calcium excretion (increasing renal
reabsorption).
Stimulating resorption of calcium from bone
•
•
•
Instrumental in the growth, hardening and repair of bones.
Too much vitamin D, however, can increase calcium losses from bone
Vitamin D is essential for normal insulin secretion by the
pancreas and therefore control of blood sugar levels.
48
When vitamin D goes abnormal
• Too little (northern latitudes) leads to Vit D
deficiency:
– Rickets (bone deformities in children)
– Osteoporosis
– Osteomalacia (weak bones)
– Demineralization of bones
• Too much (5 times the RDA, chronically): It
is most toxic of the vitamins.
– Nausea, thirst, loss of appetite, stupor
– Hypercalcemia: calcium gets deposited in soft
tissues, arteries and kidneys.
49
Diseases caused by deficiency
• Vitamin D malnutrition may also be linked to an increased
susceptibility to several chronic diseases such as
–
–
–
–
–
–
–
–
–
High blood pressure
tuberculosis
cancer
periodontal disease
multiple sclerosis
chronic pain
depression
schizophrenia
several autoimmune diseases
• The American Pediatric Associations advises vitamin D
supplementation of 200 IU/day (5μg/d) from birth onwards.
• Liquid "drops" of vitamin D for infants.
50
Vitamin E
A family of eight different molecules. Four of the eight vitamin E molecules
are called tocopherols (alpha, beta, gamma and delta) [also known as
“Natural Tocopherols”] while the remaining four are called tocotrienols
(alpha, beta, gamma and delta). D-alpha-tocopherol is the most biologically
active in humans.
-Tocopherol
is the most potent
of the tocopherols.
51
Functions
•
Vitamin E in the form of d-alpha-tocopherol is an important fat-soluble
antioxidant, scavenging oxygen free radicals, lipid peroxy radicals and singlet
oxygen molecules before these radicals can do further harm to cells. [Free
radicals are very reactive atoms or molecules that typically possess a single
unpaired electron.]
•
New studies have revealed that the tocotrienol forms of vitamin E are even more
potent antioxidants than the tocopherol isomers.
•
Vitamin E helps maintain the structural integrity of cell membranes
throughout the body.
•
d-alpha-tocopherol has been shown to inhibit the "clumping" of blood
platelets (thus helping to avoid blood clots) and enhancing vasodilation (the
opening of blood vessels).
•
d-alpha-tocopherol protects the fat component in low-density lipoproteins
(LDLs) from oxidation and has shown moderate cholesterol-lowering
capabilities. Studies have shown that gamma- and delta-tocotrienols may be
better suited than the tocopherols at inhibiting the manufacture of cholesterol in
the liver and hence in contributing to a greater cholesterol lowering effect.
52
Vitamin E (deficiency)
•
Deficiency: rare in adults usually due to impaired fat absorption or transport;
seen usually in children (anemia, edema in infants)
– Muscular dystrophy
– Hemolytic anemia
– Dietary hepatic necrosis
•
Excess: very safe below 800 IU/day
•
Source:
– Vitamin E is present in animal fats, meat, green vegetables, nuts/seeds.
– Alpha-tocopherol is found in a number of vegetable oils, including safflower
and sunflower. It is also found in wheat germ. Soybean and corn oils contain
mainly gamma-tocopherol.
•
•
•
The major site of vitamin E storage is in adipose tissue.
Estimated requirements: 5mg/day = 0.6mg/day of unsaturated fat.
Uses:
– Hemolytic anemia in premature infants, unresponsive to B12, Fe and
folic acids.
– Macrocytic megaloblastic anemia seen in children with severe proteincalorie malnutrition.
53
The symptoms of Vitamin E deficiency
•
•
•
•
•
•
•
•
•
•
•
•
Muscle weakness
lethargy
apathy
a lack of
vitality
indigestion
muscle cramps
inability to concentrate
irritability
disinterest in physical
activity
red blood cell breakage
anemia
neurological problems
• An increasing body of
evidence is emerging to
implicate free radical
activity in the
pathogenesis of
periodontal breakdown.
• Inadequate antioxidant
availability could either
predispose the host to
the disease, or modify
the progression of a
pre-existing disease.
54
Free Radicals - the Metabolic Oxidizers
Free radical = unpaired electron very reactive
.
OH
OH
.
OH
OH
Oxygen radicals: Hydroxy (HO•) / Peroxy (HOO•)
55
An antioxidant is a chemical so easily
oxidized itself that it protects others from oxidation.
OH
and / or
Double Bond
eg. Vitamin A
Phenol
eg. Vitamin E or C
56
Antioxidant
The antioxidant
neutralizes a free
radical by donating an
electron.
57
Vitamin K
• The "K" in vitamin K comes from the German
word "koagulation," which refers to blood
clotting (coagulation).
• Vitamin K is essential for the functioning of
several proteins involved in normal blood
clotting.
• There are several forms K1-K7
58
Vitamin K1 (Phylloquinone)
• Naturally occurring vitamin K is absorbed from the
intestines only in the presence of bile salts and other lipids
through interaction with chylomicrons. Therefore, fat
malabsorptive diseases can result in vitamin K deficiency.
• Present in green leafy vegetables like lettuce, parsley,
spinach and various greens (beet and mustard). Broccoli
and certain vegetable oils (soybean, cottonseed, and olive).
are also a good source of vitamin K1.
__
59
Vitamin K2 (Menaquinone)
• Vitamin K2 is a group of compounds called the "menaquinones."
• Synthesized by intestinal bacteria "n" can be 6, 7 or 9 isoprenoid
groups.
– The number of isoprene residues in the side chain of the vitamin
K2 molecule designate the individual menaquinone compounds,
e.g., menaquinone-4 (MK-4) has four isoprene units in the side
chain of vitamin K2; menaquinone-7 (MK-7) has seven isoprene
units in the side chain.
• Vitamin K2, which is the most biologically active form of vitamin K, is
found in egg yolks, butter, liver, cheddar cheese and yogurt.
• It has been suggested that products like yogurt, may help to increase
the functioning of these useful bacteria.
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Vitamin K3 (Menadione)
• The synthetic (man-made)
vitamin K3 is water soluble
and absorbed irrespective
of the presence of
intestinal lipids and bile.
Uses : essential cofactor in blood clotting.
Excess: Dangerous if taking anti-coagulants.
Hemolytic anemia, jaundice in infants.
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Functions
1. Blood coagulation
•
•
–
–
Post-translational carboxylation of some glutamate
residues in blood factors.
Vitamin K is needed for the body to make four of the
blood's coagulation factors, including prothrombin
(also known as factor II), proconvertin (factor VII),
Christmas factor (factor IX) and the Stuart-Power
factor (factor X).
It occurs in the liver
Vitamin K has to change to Hydroquinoine to function
as coenzyme for carboxylase.
2. Calcium binding proteins
–
Carboxylation of specific glutamate residues in
calcium binding proteins.
3. Role in oxidative phosphorylation
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Prothrombin -Carboxylation
63
Vitamin K role in -Carboxylation
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Deficiency
1. Prolonged use of antibiotics
2. Malabsorption and biliary tract obstruction
3. Spoilt sweet-clover hay
– Contains dicumarol (vit K antagonist)
4. Short circuiting of the bowel
5. In immediate post-natal infants
•
–
–
–
(bruising/bleeding in infants).
Sterile bowels (no intestinal microflora)
Low Vit K in mothers milk
Hemorrhagic disease of the newborn.
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Too Much Broccoli !
Two women with diseases characterized by abnormal blood
clotting did not improve when they were given Warfarin.
When questioned about their diets, one woman reported
that she ate at least a pound of broccoli every day, and the
other ate broccoli soup and a broccoli salad every day.
When broccoli was removed from their diets, warfarin
became effective in preventing the abnormal clotting of their
blood.
Because broccoli is high in vitamin K, these patients had
been getting enough dietary vitamin K to compete with the
drug, thereby making the drug ineffective.
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What do vitamins do?
•
•
•
•
Metabolically they have diverse functions as:
Coenzymes (B vitamins, vitamin K)
Hormones (retinoic acid, vitamin D)
Modulators or regulators of growth and
development (retinoic acid, folic acid)
• (apparently non-specific) antioxidants
(Vitamins C and E)
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•
•
•
•
Vitamin C:
Bleeding gums
Loose teeth
Poor healing
68
Cofactors and coenzymes
69
Other coenzymes
70
Coenzyme Q = Ubiquinone
•
•
•
•
A lipid in inner membrane of mitochondria.
Moves freely within membrane.
Carries electrons.
Coenzyme Q10 (CoQ 10) or ubiquinone is essentially a vitamin or
vitamin-like substance.
– Found in small amounts in a wide variety of foods.
– It is synthesized in all tissues.
– The biosynthesis of CoQ10 from the amino acid tyrosine requires at least
eight vitamins and several trace elements.
• Coenzyme Q10 is the coenzyme for at least three mitochondrial
enzymes (complexes I, II and III) as well as enzymes in other parts
of the cell.
• CoQ10 has been studied in its reduced form as a potent antioxidant.
2H++2e
Coenzyme Q
Coenzyme Q
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Coenzyme Q - 'promoted' to a Vitamin?
O
CH3O
CH3
CH3
CH3O
O
C
H2 C
H
C
H2
H
10
A vital 'transport agent' in the use of oxygen to generate
energy, especially in the heart muscle.
Supplements do aid in many forms of heart disease,
gum disease, BUT >> slows Parkinsons/Alzheimers/
aging, relieves allergies, boosts athletic performance
72
and immunity, aids weight loss ?!
Causes of Deficiency
•
•
Significantly decreased levels of CoQ10 have
been noted in a wide variety of diseases in
both animal and human studies.
CoQ10 deficiency may be caused by
1.
2.
3.
Insufficient dietary CoQ10.
Impairment in CoQ10 biosynthesis.
Excessive utilization of CoQ10 by the body
•
Increased body consumption of CoQ10 is the presumed
cause of low blood CoQ10 levels seen in excessive
exertion, hypermetabolism, and acute shock states.
4. or any combination of the three.
5. Drugs can cause CoQ deficiency
•
•
HMG-CoA reductase inhibitors used to treat elevated blood cholesterol levels by
blocking cholesterol biosynthesis also block CoQ10 biosynthesis.
The resulting lowering of blood CoQ10 level is due to the partially shared
biosynthetic pathway of CoQ10 and cholesterol.
73
Phytochemicals
Non-nutrient compound
Found in plant-derived foods and have biological activity
in the body.
Some categories:
Antioxidants (anti-aging/cancer/heart disease?) catechins (berries, green/black tea), lycopene
(tomatoes,watermelon), bioflavanoids (citrus
fruit, grapes), coenzyme Q (nuts,oils).
Estrogen mimics (cancer inhibitors?) indoles (broccoli, cauliflower), isoflavones
(legumes), lignans & omega-3- fatty acids
(canola, flaxseed), genistein (soy).
74
Lycopene = red pigment in tomatoes, red
grapefruit, watermelon
75
Plant Pigments = Potent Antioxidants
Almost 2000 known plant pigments. >800 flavonoids,
~450 carotenoids and ~150 anthocyanins.
Red (lycopene) – tomatoes, pink/red grapefruit,
watermelon, guava, red peppers.
Red/Blue/Purple (anthocyanins) – red/blue grapes,
blue-/straw-/raspberries, beets, cherries,
egg plant, plums, red cabbage.
Orange (carotene) – squash, pumpkin, yams,
carrots,
mango, cantaloupe.
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Plant Pigments = Phytochemicals
Orange/Yellow (cryptoxanthin) – peach, orange,
nectarine, papaya.
Yellow/Green (lutein), zeaxanthin =
especially good for health of eyes) –
corn, cucumber skins, yellow/green
peppers, green beans/peas, spinach,
honeydew melon, kiwi, romaine lettuce,
77
Vitamin O - the next miracle supplement!
Recipe: Take 8oz water, add a pinch of salt, bubble
in oxygen/(air?) for 15 seconds then sell
for $20(US) + shipping/handling.
Or maybe you would like to visit an 'oxygen bar'?
Get fined for US$400,000 (for 'fraudulent claims'),
change the wording and keep on selling. To-date an
estimated 1 million bottles have been sold!
Check out the ‘Net’ under ‘vitamin O’
eg. ~first 10 entries on ‘Yahoo’ or ‘Google’
78