COENZYME AND COFACTOR

(WEEK 2)
 PARTS OF ENZYME STRUCTURES
Enzyme (Protein)  Apoenzyme (Apoprotein)

+ Prosthetic group (non protein)  Holoenzyme (Holoprotein)
cofactor (anorganic ion) coenzyme (organic molekule)

S  active site  active centre  catalytic subunit

E  allosteric enzyme S (substrate) & A (activator)/ I (inhibitor)
A/I  allosteric site  effector site  regulatory subunit
 Non allosterik enzyme  no allosteric site/effector site/regulatory subunit
 Activator may be cofactor/other substance
 Substrat binding site  identical/different with active site  non allosterik/allosterik
 VITAMIN AS SOURCE OF COENZYME

Precursor for coenzyme

● Vitamin A

Most can not be Lipid soluble

● Vitamin D vitamin
synthesized by animal/ ● Vitamin E
human → must be ● Vitamin K
obtained from diet ● Vitamin B1
● Vitamin B2
Water soluble
● Vitamin B3
vitamin
● Vitamin B5
Trace amount required → ● Vitamin B6
the synthesized ● Vitamin B12
● Folic acid
coenzymes can be recycle ● Vitamin C
LIPID SOLUBLE VITAMIN AND THEIR ACTIVE COENZYME STRUCTURES

LIPID SOLUBLE VITAMIN: ADEK

Lipid Soluble Vitamin : 1. Vitamin A

Function:
Visual pigment of the vertebrate eye
Hormone precursor
Deficiency:
night blindness
xerophthalmia
Retarded development and growth
Dryness of the skin, eyes, and mucous membrane
Sources:
Fish liver oil
Eggs
Whole milk
Butter
β-carotene, the pigment that gives carots, sweet potatoes, and other yellow vegetables their
characteristic color, can be enzymatically converted to vitamin A
Coenzyme structures and mechanisms:
 H3C
CH3 CH3 CH3 β-Carotene
(Provitamin A) H3C Structures and action
mechanisms of
CH3 vitamin A
CH3 CH3 CH3
CH3
O2 β-carotene
R O Bile acid dioxygenase
H3C Hormon signal to
CH3 O CH3 CH3
H3C epithelial cell.
Regulate gene
CH3 expression in the
CH3 CH3 CH3 epithelial cell,
CH3
H3C including skin
H3C Active ingredient in
CH3 CH3 CH3 H HO the drug
2 C tretinon(Rectin-A).
C OH H
2 CH3 CH3 CH3
CH3 Retinol (vitamin A1)
CH3 CH3 CH3 CH3
OH
C
Retinal NADP (NAD )
- -
O
CH3 Retinoic acid
reductase/oxidase
NADPH (NADH), H+ CH3
FAD
CH3 CH3 CH3 Retinal Isomerase CH3 CH3 NAD
H H
C Opsin
O C O
CH3 CH311-cis-Retinal
all-trans-Retinal CH3
CH3 Rhodopsin CH3
hυ
THE FUNCTION OF RETINAL/VITAMIN A IN VISION TRANSDUCTION
 Lipid Soluble Vitamin : 2. Vitamin D
Function: calcium and phosphate metabolism , prohormone
Deficiency: defective in bone formation, the disease rickets, osteomalca
Sources: animal (vit D3) and yeast (vit. D2)
Coenzyme structures and mechanisms:
X = (CH2)3 → 7-dehydrocholesterol → cholecalsiferol (D3) ←
X = CH=CH-CH(CH3) → ergosterol → ergocalsiferol (vit. D2) → commercial product
formed by irradiation of the ergosterol of yeast, commonly added to milk, butter as a
dietary supplement

H–C–X–CH(CH3)2 H–C–X–CH(CH3)2
CH3 25 CH3 25
H3C 9 h H2 C
1 10 1
B photolysis B
HO 3 5 7

A hormone that regulates gene in liver

and OH
expression, such as:
- turning on the synthesis of an kidney
H–C–X–CH(CH3)2
intestinal Ca2+ binding protein to CH3 25
increase the calcium uptake
HO H2 C
- turning on/off the synthesis of Ca2+
binding proteins in kidney and 1
B 1,25-Dihydroxycholecalciferol
bone to adjust calcium levels HO (1,25-dihydroxyvitamin D3)
 Lipid Soluble Vitamin : 3. Vitamin E (Tocopherol)
Functions:
 fertility factor in reproduction
 natural antioxidant
 defense against oxidation of polyunsaturated fatty acids
 act synergistically with selenium of glutathione peroxidase
Deficiency: neurological disorder, anemia, scaly skin, muscular weakness and wasting, sterility.
Deficiency in human is very rare, the principle symptom is fragile erythrocytes.
Sources: egg and vegetables oil, and are especially in wheat germ. Tocopherols are hydrophobic,
associate with cell membranes, lipid deposit, and lipoproteins in the blood
Coenzyme structures and mechanisms:
CH3 CH3 CH3 CH3
8 1 CH3
H3 C 7 2 (CH2)3-CH(CH2)3-CH(CH3)2-CH-CH3 oxidation
HO 6 5 α- tocopherol
4 3 CH3
CH3 8
CH3
OH O C=O
substitution H3C 7 2
HO 6 5 3
C
Naturally occurring 4
CH3 CH2-CH2
tocopherols of dietary significance
Tocopherol Substituents Tocopherols group, contain a substituted aromatic ring
and a long isoprenoid chain. The aromatic ring reacts
 5,7,8-Trimethyl tocol with and destroy the most reactive forms of oxygen
 5,8-Dimethyl tocol radicals and other free radicals, protecting unsaturated
fatty acids from oxidation and preventing oxidative
 7,8-Dimethyl tocol damage to membrane lipids, which can cause cell
fragility
 8-Methyl tocol
 Lipid Soluble Vitamin : 4. Vitamin K
Functions:
 biosynthesis of blood clothing factor
 cofactor of the carboxylase that forms -carboxyglutamate in precusor protein
 antidote to poisoning by dicumarol-type durgs
Deficiency: slow blood clothing, neurological disorder, anemia
Sources: K1 found in green leaves (alfala), K2 formed by bacteria residing in vertebrate intestine
Coenzyme structures and mechanisms:
O
CH3 The aromatic ring undergoes a cycle of oxidation and reduction during
the formation of active prothrombin, a blood plasma protein essential in
H blood clot formation. Prothrombin is a proteolytic enzyme that splits
peptide bonds in the blood protein fibrinogen to convert it to fibrin, the
O insoluble fibrous protein that holds blood clot together.
vit. K3 (menadione )
H = CH2CH=C(CH3)-CH2-(CH2-CH2-CH(CH3)-CH2)3-H = phylloquinone (vit.K1);
H = (CH2CH=C(CH3)-CH2)n-H = menaquinone (vit. K2), n = 6, 7, or 9
phospholipid
Carboxylation of Ca 2+

glutamate residue

CO2 Chelation of
calcium ion by the
vitamin K -carboxyglutamyl
residue in clotting
vitamin K- factor proteins
dependent
carboxylase
 The oxidation and reduction cycle of vitamin K-aromatic ring

oxidation
Other electron carrier molecules:
Warfarin
Ubiquinone: a mitochondrial
electron carrier
Plastoquinone: a chloroplast
electron carrier
Dolichol: a sugar carrier

reduction

(A synthetic blood anticoagulant,

inhibits the formation of active
prothrombin)
WATER SOLUBLE VITAMIN AND THEIR ACTIVE COENZYME STRUCTURES

Vitamin Coenzymes
precursors Functions
(Active form)
Thiamin (B1) Thiamin Pyrophosphate Hydroxyl or alkyl group
(TPP) transfer
Riboflavin
(B2) (FAD), (FMN) Redox: H- (2e-, 1H+)

Niacin (B3) (NAD+), (NADP+) Redox: H- (2e-, 1H+)

Pantothenic
acid (B5) Coenzyme A Acyl- transfer

Pyridoxine
(B6) Pyridoxal phosphate (Py) Amine-transfer

Biotin Carboxybiotin Carboxyl-transfer

Cobalamin Methyl/deoxyadenosylcobal Methyl-transfer
(B12) amin
Folic acid Tetrahydrofolic acid (THF)
Carbon atom-transfer
RATE OF
ACTIVE-PROTEIN ACTIVITY METABOLISM
 Water Soluble Vitamin : 1. Vitamin B1 (Thiamin)
Functions: CO2 transfer (oxidative decarboxylation H Active site
of -keto acid, transketolase in pentose NH2
phosphate pathways, etc.) S O O
Deficiency: beri-beri CH2 N
Sources: meat, beans, and vegetables
CH2-CH2O-P-O-P-O-
H3 C CH3 O- O-
Coenzyme structures and mechanisms:
H TPP (thiamine pyrophospate)
NH2
S
CH2 N
CH2-CH2OH
H3 C CH3 Chain A
thiamine (vitamin B1)
→ thiazole ring is used as aldehide carrier
(through covalent bond) in amino
acid deamination/degradation
O
H H3C C H
O acetaldehyde Chain B
H3C C H E-TPP Mg2+
NH2 O
S O O Piruvat decarboxylase
CH2 N
CH2-CH2O-P-O-P-O- H3C C CO2-
H3 C CH3 O- O- HCO3-
E-TPP-acetaldehyde Piruvat
 Water Soluble Vitamin : 2. Vitamin B2 (riboflavin) O
Functions: redox reaction of -tioester-double bond, e.g. fatty acid N
biosynthesis H3 C NH
Deficiency: cheilosis, glossitis, seborrhea, photophobia, etc.
O
H3 C N N
Sources: yeast, meat (liver and kidney), beans, and leafy vegetables
O O
Coenzyme structures and mechanisms: Active site
H3 C N NH H3 C N (flavin/isoa
NH
O O lloxaazin
H3 C N N H3 C N ring)
N

R R

Riboflavin (vitamin B2)

• FAD = FMN + AMP

• FADH2 = FMNH2 + AMP Coenzyme Flavin
mononucleotide (FMN)
Coenzyme Flavin Adenine
Dinucleotide (FADH2)
 Examples of Flavoproteins
FAD
HDF

FAD

Photolyase
Flavin
Flavoprotein enzymes nucleotide
required
Acyl-CoA dehydrogenase FAD
Thioredoxin
Dihydrolipoyl dehydrogenase FAD
reductase
Succinate dehydrogenase FAD
Glycerol 3-phosphate dehydrogenase FAD
Thioredoxin reductase FAD
Cytochromes
Photolyases NADH dehydrogenase(Complex 1) FMN
Glycolate oxidase FMN
 Water Soluble Vitamin : 3. Vitamin B3 (niacin)
Functions: de-/hydrogenation of -keto tioester, e.g.
fatty acid degradation/biosynthesis
Deficiency: pellagra/rough skin dermatitis, diarrhea, Active site
dementia, blacktongue (in dog) H O (nicotinamide ring)
Sources: beans C-NH2
Coenzyme structures and mechanisms:
O N+ NAD+ : X = ―OH
O O
C-NH2 NADP+ : X = ─O―PO3H-
Nicotinamide H H
O P O- H NADP = NAD + P
N (niacinamide) NH2
OH HX (Oxidized form)
O O
N N + H+
C-OH R O P O-
(Reduced form)
Nikotinic acid N
N (niacin) N NADH, NADPH
O O
H H
General reaction H H
OH H
H+

S + + H+
Dehydrogenized
Substrate NADP+, or NAD+ substrate NADPH, or NADH
 Examples of NAD(P)+-dependent dehydrogenase

NAD(P)+-dependent
dehydrogenase Coenzyme

Isocitrate
dehydrogenase NAD+

A-Ketoglutarat
dehydrogenase NAD+

Glucose 6-phosphate
dehydrogenase NAD+

Malate dehydrogenase NAD+ NAD

Glutamate NAD+ or
dehydrogenase NADP+ NAD
Glyceraldehide 3-
phosphate NAD+
dehydrogenase
Lactate dehydrogenase NAD+
Alcohol Glyceraldehide 3-phosphate dehydrogenase
dehydrogenase NAD+
 Water Soluble Vitamin : 4. Vitamin B5 (pantothenic acid)
Functions:
acyl-radicals carrier in: citric acid cycle, fatty acid oxidation/synthesis, drug acetylation, and
cholesterol synthesis
Deficiency: rare (widely abundant in foods). Burning foot syndrome in POW due to reduced
capacity for acetylation
Sources: abundant in animal tissues, whole grain cereals, and legumes
Coenzyme structures and mechanisms:
Pantoic acid B-alanine

thioethanolamine

vitamin B5 (pantothenic acid)

ADP
Coenzyme A
(CoA)
active form

2NADPH, 2H+ 2NADP

 Water Soluble Vitamin : 5. Vitamin B6 (pyridoxin)
Functions:
reduction amination in amino acid reaction/biosynthesis
Deficiency: dermatitis, anemia, epilepsi HO CH2OH
Sources: liver, mackerel, avocados, bananas, meat, vegetables, eggs
Coenzyme structures and mechanisms: H3 C N
pyridoxin

HO CH2

α-keto acid H3C N HO CH2OH

pyridoxaminephosphate
Reduction Transaminase Oxidation H3 C N
amination or amino deamination pyridoxamine
transferase

HO CH2 HO CH2OH

N H3C N
H3 C pyridoxal
α-amino acid pyridoxalphosphate
Coenzyme (active form) Vitamin B6
 Detail mechanisms of amine transfer
-
base
H H
H C NH2 H C N
HO CH2 + HO CH2
α-keto acid
H3 C N N
R' H3C Ketimine
Hbase
H C N
HO CH2 HOH

H 3C N
H H C N H C N
HO CH2 HO CH2

H3 C N H3C N
R' H - H
base
α-amino acid NH2 Aldimine Quinoid
 Water Soluble Vitamin : 6. Biotin
Funtions:
carboxylation (CO2 transfer)
Deficiency: depression, halucination, muscle pain, and dermatitis, accumulation of substrates of
biotin-dependent enzyme (lactate, -methylcrotonate, -hydroxyisovalerat, and -hydroxy-
propionate) that can be detected in urine
Sources: widely distributed in natural foods
Coenzyme structures and mechanisms: ATP
+

HCO3-

biotin biotin-enzyme (BE) (active form) +

O O Mg2+
-
O O P O-
O-
Carbonic
P phosphoric ADP
anhydride
oxaloacetate pyruvat

BE
CO2-BE
THE MOLECULAR MECHANISM OF BIOTIN FUNCTION
 Water Soluble Vitamin : 7. Vitamin B12

Funtions:
methyl transfer i.e. in citric acid cycle, gluconeogenesis
Deficiency: megaloblastic anemia
Sources: microorganisms (yeast, rumen organisms), animal liver
Coenzyme structures and mechanisms:

methionine
synthetase

methyl-H4folate methylacobalamin B12 H4folate

hydroxocobalamin B12

deoxyadenosylcobalamin B12
methylmalonyl-CoA
mutase
 Water Soluble Vitamin : 8. Folic acid
Funtions:
one carbon-atom transfer folic
acid
, , , ,
NADPH, H+
Deficiency: megaloblastic anemia NADP+
Sources: yeast, liver, leafy vegetables
Coenzyme structures and mechanisms:

active
site

pteridine dihydrofolic acid

glutamic
acid NADPH, H+

p-aminobenzoic NADP+
acid (PABA)

pteroy (pteroic acid)

folic acid
H4 folate
(tetrahydrofolic acid)
 THE MECHANISM OF ONE CARBON-ATOM TRANSFER

glycine
N5,N10-Methylene-H4 folate
serine

tetrahydrofolic acid

tetrahydrofolic acid

deoxythymidylic acid deoxyuridylic acid

 Water Soluble Vitamin : 9. Vitamin C (Ascorbic acid)
Functions:
donor of reducing equivalents in collagen synthesis, tyrosine degradation, epinephrine
synthesis, bile acid formation, steroidogenesis, iron absorption, antioxidant
Deficiency: scurvy, subcutaneous, hemorrhages, muscle weakness, swollen gum, and loose teeth
Sources: orange, tomatoes, green pepper
Coenzyme structures and mechanisms:
HO OH
O CHCH2OH
OH gulonolactone -ketoglutarat succinate

Enzyme absent in primate Fe2+

(human and some animals), O2
only in plant ascorbate
HO OH
CHCH2OH Pro Pro
O
OH Vitamin C (ascorbic acid ) OH
2H Hydroxylase reaction in the
present of vitamin C
O O
O CHCH2OH
OH dehydroascorbic acid
 MINERALS AS SOURCE OF COFACTOR

Inorganic mineral elements that have a function in the

body must be provided in the diet. When insufficient,
deficiency symptoms may arise, and if present in excess
they may be toxic

Minerals are required for both physiologic & biochemical

functions
 MINERAL INTAKE

 Many of the essential minerals are widely distributed in foods

 Most people eating a normal mixed diet are likely to receive adequate intakes.
 The amounts required vary from the order of grams per day for sodium and calcium,
through milligrams per day (eg, iron) to micrograms per day for the trace elements.
 In general, mineral deficiencies are encountered when foods come from one region,
where the soil may be deficient in some minerals, eg, iodine deficiency.
 Where the diet comes from a variety of different regions, mineral deficiencies are
unlikely. However, iron deficiency is a general problem because if iron losses from
the body are relatively high (eg, from heavy menstrual blood loss), it is difficult to
achieve an adequate intake to replace the losses.
 Foods from soils containing high levels of selenium cause toxicity, and increased
intakes of common salt (sodium chloride) cause hypertension in susceptible
individuals.
CLASSIFICATION OF ESSENTIAL MINERALS ACCORDING TO THEIR FUNCTION
SOME INORGANIC ELEMENTS THAT SERVE AS COFACTORS FOR ENZYMES