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Cofactors

Cofactors are organic or inorganic molecules that are


required for the activity of a certain conjugated enzymes
Apoenzyme (inactive): enzyme without cofactor
Holoenzyme (active): enzyme with cofactor
Inorganic cofactors: essential ions
Organic cofactors: coenzymes

I. Essential Ion Cofactors

Metal activated enzymes require or are stimulated by addition of


metal ions - usually monovalent cations (e.g. K+, Na+) and divalent
cations (e.g. Mg2+, Zn2+)

Metal ions of metalloenzymes cations that are tightly bound to


enzyme and participate directly in catalysis usually transition
metals (e.g. Fe, Zn, Cu, Co)

Metalloenzymes (with bound metal ions at active sites)


Carbonic anhydrase
- A Zn2+ metalloenzyme
- CO2 + H2O bicarbonate

CO2

H2O

Iron sulfur clusters in enzymes involved in oxidation-reduction


- Fe complexed with S
- Accept or donate electrons

II. Coenzymes
Cosubstrates- altered in a reaction and dissociated from active site
- regenerated to original structure in a subsequent reaction
- transfer chemical groups among different enzyme reaction.
Prosthetic groups- remains bound to enzyme
- must return to original form
Both cosubstrates and prosthetic groups supply reactive groups not
present on the active site amino acid side chains
Vitamin derived coenzymes

Must be obtained from diet


Synthesized by microorganisms and plants
Vitamin deficiencies lead to disease state
Most vitamins must be enzymatically transformed to function as a
coenzyme

What about vitamin B4 and B8?

1. ATP and other nucleotide coenzymes


- Supply chemical group to other substrates
A. ATP:

Nucleotidyl group (AMP)


Phosphoryl groups

ATP + substrate

SubstrateP

+ ADP

ATP + substrate

SubstratePP + AMP

ATP + substrate

SubstrateAMP + PPi

B. S-Adenosylmethionine (SAM):

Methionine + ATP

SAM
Methyl
group

SAM is a donor of methyl group in biosynthetic reaction


Example:
SAM

C. Nucleotide sugar phosphates


-

Involved in carbohydrate metabolism


UDP-glucose: carrier of glucose for transfer to other substrate

Formation of UDP-glucose:

Glucosyl group

2. NAD+ and NADP+


-

Nicotinamide coenzymes
Nicotinamide adenine dinucleotide (phosphate)
Precursor nicotinic acid (Niacin, B3)
Tryptophan can be degraded to niacin
Oxidation-reduction reactions

3. FAD and FMN


-

Flavin coenzymes
Flavin adenine dinucleotide (FAD); Flavin mononucleotide (FMN)
Precursor riboflavin (B2)
Prosthetic group
Oxidation-reduction reactions
FAD

Riboflavin

= H in
FMN

4. Coenzyme A and acyl carrier protein (ACP)


-

Transfer of simple carboxylic acids and fatty acids


Free thiol (-SH) group for acyl group attachment

Co-enzyme A

Vitamin B5

ACP

5. Thiamine Diphosphate (TDP or TPP)


-

Made from thiamine (B1)


Prosthetic group for enzymes in decarboxylation/carboxylation

- first Vitamin discovered (Vital amine = Vitamin)

TDP in decarboxylation
of pyruvate to
acetylaldehyde:

6. Pyridoxal 5-phosphate (PLP)


-

Made from Vitamin B6


Prosthetic group for enzymes catalyzing reactions involving amino acids

Vitamins of the B6 family

PLP in transamination reaction

7. Biotin
-

Vitmain B3
Carboxyl group transfer reaction
ATP-dependent carboxylation
Prosthetic group
Bound to lysine residue in enzyme

Biotin in ATP-dependent carboxylation of pyruvate

8. Tetrahydrofolate (THF)

- Folate is converted to THF by the addition of 4 hydrogens to the pterin ring.


- Important in transfer of one-carbon units (N10 and N5 are involved)
- THF Has a poly-glutamate tail formed by gamma-carboxyl and alpha amino
groups (unusual peptide bond).

One-carbon
derivatives of
THF:

9. Cobalamin (B12) coenzymes


-

B12 is the largest B vitamin


Corrin ring with cobalt cation
Coenzymes: methylcobalamin and adenosylcobalamin

Cobalamin coenzymes
- Participate in reactions involving intramolecular rearrangements, methyl
group transfer, etc.
1. Intramolecular rearrangement:

2. Methyl group transfer:

5-methylTHF

THF

Cobalamin

Methylcobalamin

Methionine

Homocysteine

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