Download vitamins and coenzymes

2016-11-01
VITAMINS AND COENZYMES
Structures and functions
Department of General Chemistry
Poznan University of Medical Sciences
Enzyme Cofactors
• A simple enzyme is an active enzyme that consists only of
protein.
• Many enzymes are active only when they combine with
cofactors such as metal ions or small molecules.
• A coenzyme is a cofactor that is a small organic molecule
such as a vitamin.
Cofactors and Coenzymes
• Active enzyme / Holoenzyme:
– Polypeptide portion of enzyme (apoenzyme)
– Nonprotein prosthetic group (cofactor)
• Cofactors are bound to the enzyme for it to maintain the
correct configuration of the active site
– Metal ions
– Organic compounds
– Organometallic compounds
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Cofactors
Cofactor = Non protein Group
needed to ‘activate
activate’ apoenzyme
Co2+
E
ES
Co2+
Apoenzyme
•protein portion
•Inactive
S
Coenzymes
= organic molecule that temporarily binds to
apoenzyme in order for it to work.
+
apoenzyme
coenzyme
holoenzyme
often
Vitamins
Metal ion catalysts
One-third of all known enzymes needs metal ions to work!!
1. Metalloenzymes: contain tightly bound metal ions: I.e. Fe++, Fe+++,
Cu++, Zn++, Mn++, or Co++.
2. Metal-activated enzymes- loosely bind ions Na+, K+, Mg++, or Ca++.
They participate in one of three ways:
They bind substrates to orient then for catalysis
Through redox reactions gain or loss of electrons.
Electrostatic stabilization or negative charge shielding
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Types of cofactors
• Essential ions:
• Activator ions (loosely
bound)
• Metal ions of metalloenzymes (tightly bound)
Coenzymes
• Cosubstrates ((loosely
bound)
• Prosthetic group (tightly
bound)
Activator ions (loosely bound)
The following structures of the ATP-magnesiumcomplex have been proposed:
Mg2+ ion neutralizes some of the charges and reduces non-specific
interaction and influences ATP conformation
Reaction does not take place in the absence of Mg-ions, but Mg2+ is not a
part of catalytic core
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Metal Ions as Cofactors
• Many active enzymes
require a metal ion.
• Zn2+, a cofactor for
carboxypeptidase,
stabilizes the carbonyl
oxygen
during
the
hydrolysis of a peptide
bond.
Coenzyme can also be classified by their source
1.
Metabolite coenzymes: are synthesized from common
metabolites e.g ATP, S-adenosylmethionine
2.
Vitamin-derived coenzymes: are derivatives of vitamins,
which are compounds that cannot be synthesized by
animals and must be obtained as nutriens
Adenosine triphosphate (ATP)
• ATP can donate:
phosphoryl,
pyrophosphoryl, adenyl
(adenosine monophosphate
=AMP), or adenosyl groups in group transfer reactions.
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Cyclic Adenosine Monophosphate cAMP
Cyclic AMP is produced by an integral membrane enzyme, adenylyl cyclase
Cyclic Adenosine Monophosphate (cAMP)
ATP is also the source of several other metabolite
coenzyme
• One, S-adenosylmethionine, is
synthesized by the reaction of
methionine with ATP
• The positively charged
sulfonium is highly reactive
• S-adenosylmethionine is the
donor of virtually all the
methyl groups used in
biosynthetic reactions
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S-ADENOSYLMETHIONINE
S-adenosylmethionine (SAM) as a donor of
methyl group
• For example, it is required for the conversion of the
hormone norepinephrine to epinephrine
• Vitamins are classified into two groups by solubility:
water- soluble and fat-soluble
• Water- soluble vitamins have polar groups such as
-OH and -COOH, which make them soluble in the
aqueous enviroment of the cells
• Fat-soluble vitamins are nonpolar compounds, which
are soluble in the lipid components of the body (cell
membrane
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Thiamine (Vitamin B1)
Was the first B vitamin
identified.
• Thiamine is composed of a
substituted thiazole ring
joined to a substituted
pyrimidine by a methylene
bridge
• Dietary sources of thiamine
include liver, yeast, whole
grain bread, cereals, and milk
Thiamine (Vitamin B1)
• Deficiency results in beriberi (fatigue, weight loss, and nerve
degeneration).
• Beriberi is caused by carbohydrate-rich/low thiamine diets,
e.g. polished rice or other highly refined foods
• Wernicke-Korsakoff syndrome, a striking neuropsychiatric
disorder is caused by lack thiamine in the diet. It is found
frequently in chronic alcoholics consuming little other food.
Thiamine (Vitamin B1)
• Is part of the coenzyme
thiamine pyrophosphate
(TPP).
• TPP coenzyme is required by
enzymes in the oxidative
decarboxylation of α-keto
acids
( e.g. pyruvate dehydrogenase
requires TPP)
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Riboflavin (vitamin B2 )
• Riboflavin consists of
the five-carbon alcohol
ribitol linked to a
nitrogen atom of
isoalloxazine
• Sources of vitamin B2:
milk, eggs, liver, green
leafy vegetables.
• Made of the sugar alcohol
ribitol and flavin.
Isoalloxazine ring
Riboflavin (Vitamin B2)
Riboflavin is:
• Part of the coenzymes flavin adenine dinucleotide (FAD) and
flavin mononucleotide (FMN).
• Riboflavin deficiency symptoms include dermatitis, cheilosis
(fissuring at the corners of the mouth), and glossitis (the
tongue appearing smooth and purplish).
• Needed for good vision and healthy skin.
FAD and FMN coenzyme are derived from riboflavin
FAD contains AMP and a pyrophosphate linkage
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Niacin (Vitamin B3)
Niacin:
• Is part of the coenzyme
nicotinamide adenine
dinucleotide (NAD+) involved in
oxidation-reduction reactions.
• Deficiency can result in
dermatitis, muscle fatigue, and
loss of appetite.
• Is found in meats, rice, and
whole grains.
Nicotinamide
O
C
OH
N
Nicotinic acid
(niacin)
Clinical Significances of Nicotinic Acid (Niacin)
• A diet deficient in niacin (as well as tryptophan) leads
to glossitis of the tongue, dermatitis, weight loss,
diarrhea, depression and dementia.
• The severe symptoms, depression, dermatitis and
diarrhea, are associated with the condition known as
pellagra.
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NAD+/NADH
Nicotinamide adenine
dinucleotide (NAD+) is
used in many biological
redox reactions
•Contains:
1)nicotinamide ring
2) Adenine ring
3) 2 sugar-phosphate
groups
The coenzymes most commonly used by enzymes to catalyze redox
reactions:
oxidizing
agents
reducing
agents
NAD+ almost always acts as cosubstrate for
dehydrogenases
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Two Other Adenine
Dinucleotide Coenzymes
Pantothenic Acid (Vitamin B5)
Pantothenic acid:
•
Is part of coenzyme A needed for energy production as well as glucose
and cholesterol synthesis.
•
Deficiency can result in fatigue, retarded growth, cramps, and anemia.
•
Is found in salmon, meat, eggs, whole grains, and vegetables.
CH3 OH O
HO CH2 C
O
CH C N CH2
CH3
CH2 C OH
H
It is formed by combination of pantoic acid and β-alanine
Coenzyme A (CoA)
The reactive center is the
thiol group.
Like the active coenzymes of so many
other water-soluble vitamins, CoA
contains an adenine nucleotide.
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The B6 family of vitamins consists of three closely related molecules that
differ only in the state of oxidation or amination of carbon bound to
position 4 of the pyridine ring
Pyridoxine (Vitamin B6)
• Pyridoxine and pyridoxal are two forms of vitamin B6, which are
converted to the coenzyme pyridoxal phosphate (PLP).
•
•
Deficiency of pyridoxine may lead to dermatitis, fatigue, and anemia.
Sources of the vitamin are wheat, corn, egg yolk, liver,
PLP is required in the transamination and decarboxylation of of amino acids
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Pyridoxal Phosphate: Vitamin B6
Required by enzymes that catalyze certain transformations of
amino acids (is the prosthetic group for many enzymes)
PLP is prosthetic group of enzyme ((Schiff base
bond)
In the absence of an amino acid as a substrate the aldehyde group of PLP is bound at
the amine group (Schiff base bond) by a particular lysine residue on the active site of
the aminotransferase.
Cobalamin (Vitamin B12)
• Cobalamin consists of four
pyrrole rings with a Co2+
• It is a coenzyme involved in
the transfer of methyl
groups,
acetyl
choline
synthesis and red blood cell
production
• A deficiency in vitamin B12
can lead to pernicious
anemia and nerve damage
• Dietary sources include
beef, chicken, fish and milk
products (strict vegans
should
take
B12
supplements)
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Intrinsic Factor (IF) is glycoprotein
•
•
Most victims of pernicious
anemia do not secrete a
necessary glycoprotein (called
intrinsic factor=IF) from the
stomach mucosa.
This protein specifically binds
cobalamin, and the cobalaminintrinsic factor complex is
absorbed by cells of the small
intestine.
Lack of IF prevents the absorption of vitamin B12 resulting in pernicious anemia
Folate (Vitamin)
The vitamin folate has three main components: a pteridin ring, a p-aminobenzoic
acid (PABA), and glutamate residue
Folic Acid (Folate)
• A deficiency of folate can
lead to abnormal red blood
cells, anemia, intestinal-tract
disturbances, loss of hair,
growth impairment,
depression
• Folic acid is found in
spinach leaves (hence the
name folium), liver, sea
food, yeast
THF
• Forms the coenzyme
THF used in the transfer
of carbon groups and the
synthesis of nucleic acids.
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Coenzyme THF (tetrahydrofolate)
The groups (R1 and R2) bound to THF are methyl, methylene, or
formyl groups
Biotin as CO2 carrier
Biotin (Vitamin H)
Biocytin
• Biotin acts as a mobile
carboxyl group carrier in a
variety
of
enzymatic
carboxylation reactions.
• In each of these, biotin is
bound covalently to the
enzyme as a prosthetic
group via the ε-amino
group of a lysine residue on
the protein (biocytin)
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Biotin: Vitamin H
Ascorbic Acid (Vitamin C)
Is found in blueberries, citrus fruits, tomatoes, broccoli, red and
green vegetables.
The carbohydrate ascorbic acid is a lactone, an internal ester in which the
C-1 carboxylate group is condensed with the C-4 hydroxyl group, forming
a ring structure
Ascorbic Acid (Vitamin C)
•
•
•
•
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.
The active form is ascorbic acid itself.
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Ascorbic Acid (Vitamin C)
• 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.
A deficiency of ascorbic acid results in SCURVY, a disease characterized
by sore, spongy gums, loose teeth, fragile blood vessels, swollen joints,
and anemia
LIPOIC ACID
•
•
•
Lipoic acid is an eight-carbon
carboxylic acid (octanoic acid) in
which two hydrogen atoms, on
C-6 and C-8, have been replaced
by sulfhydryl groups in disulfide
linkage.
The carboxyl group of lipoic acid
is covalently bound to the ε-amino
group of a lysine residue of a
protein via an amide linkage, and
forms coenzyme lipoamide.
The
coenzyme
lipoamide
functions as a swinging arm that
carries acyl groups between active
sites
in
the
multienzyme
complexes.
Ubiquinone (CoQ)
•
•
Ubiquinone (CoQ) is a lipid soluble
coenzyme
It is a component of the electron
transport chain and participates in
aerobic cellular respiration, generating energy in the form of ATP.
•
•
Ubiquinone (CoQ) is a benzoquinone
with four substituents, one of which is
a long hydrophobic chain
This tail, which consists of 6 to 10
isoprenoid units, allows ubiquinone
(CoQ) to dissolve in lipid membranes
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Vitamin A
• Vitamin A is obtained from meats and beta-carotenes in
plants.
• Beta-carotenes are converted by liver enzymes to vitamin A
(retinol).
H 3C
B e ta -c a r o te n e
CH3
CH3
CH3
CH3
CH3
H 3C
H 3C
CH3
CH3
CH3
H 3C
CH3
CH3
C H 2O H
R e tin o l (v it a m in A )
CH3
Cis retinal
Vitamin A exists in three forms that differ in the oxidation state of
the terminal functional group: the stable alcohol retinol, the
aldehyde retinal, and retinoic acid
Retinoic acid
Cis- Retinal
The aldehyde retinal is a light-sensitive compound with an important role in vision.
Retinal is the prosthetic group of the protein rhodopsin; absorption of a photon of light by
retinal triggers a neural impulse.
Vitamin E
Vitamin E:
• Is an antioxidant in cells.
• May prevent the oxidation of unsaturated fatty acids.
• Is found in vegetable oils, whole grains, and vegetables.
• A deficiency of vitamin E is rare but may lead to fragile red blood cells
and neurological damage
CH3
HO
CH3
H3C
O
CH3
CH3
CH3
CH3
CH3
The phenol group of vitamin E can undergo oxidation to
a stable free radical.
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Vitamin D
Vitamin D (D3):
• Is synthesized in skin exposed to
sunlight.
• Regulates the absorption of
phosphorus and calcium during
bone growth.
• Deficiency can result in weakened
bones.
• Sources include cod liver oil, egg
yolk, and enriched milk.
The active form is 1,25 dihydroxycholecalciferol(D3 )
The active form of vitamin D3 is formed from vitamin D3 by two hydroxylation
reactions (in liver at C25 and kidney at C1).
Vitamin D-deficiency diseases is rickets in children and osteomalacia in adults
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Vitamin K
• Vitamin K1 in plants has a saturated side chain.
• Vitamin K2 in animals has a long unsaturated side chain.
• Vitamin K2 is needed for the synthesis of zymogens for
blood clotting.
O
O
CH3
CH3
CH3
CH3
3
O
CH3
CH3
n
O
Vitamin K1 (phylloquinone)
CH3
CH3
Vitamin K2 (menaquinone)
• Vitamin K is required in the hepatic synthesis of prothrombin
and the blood clotting factors VII, IX, and X.
• These proteins are synthesized as inactive precursor
molecules
• Formation of the clotting factors requires the vitamin
K-dependent carboxylation of glutamic acid residues forming
a mature clotting factor that contains γ-carboxyglutamate
(Gla) and is capable of subsequent activation
Prothrombin γ-Carboxylation
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Vitamin Coenzymes
Coenzyme Made
Vitamin
Thiamine
Pyrophosphate
Thiamine (B1)
Oxidative Decarboxlation
Electron Transfer
FAD, FMN
Riboflavin (B2)
tetrahydrofolic acid
folic acid
biotin
Function
amino acid metabolism
CO2 fixation
biocytin
Pantothenic Acid
Coenzyme A
acyl group carrier
Ascorbic Acid (C)
Vitamin C
Collagen synthesis
Healing
Commom Coenzymes
Coenzyme
Reaction mediated
Biotin
Carboxylation
Cobalamin (B12)
Alkylation transfers
Coenzyme A
Acyl transfers
Flavin
Oxidation-Reduction
Lipoic acid
Acyl transfers
Nicotinamide
Oxidation-Reduction
Pyridoxal Phosphate
Amino group transfers
Tetrahydrofolate
One-carbon group transfers
Thiamine pyrophosphate
Aldehyde transfer
Coenzymes
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Cofactors and coenzymes
Structures of the following compounds are obligatory
for the control test of vitamins & coenzymes
• Three forms of vitamin B6 (pyridoxal, pyridoxamine,
pyridoxine)
• Biotin and its complex with protein (biocytin)
• Vitamin C (ascorbic acid and dehydroascorbic acid)
• ATP
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