Enzymes-cofactors

Dr. Mamoun Ahram

Resources
Biochemistry. 5th edition. Berg JM, Tymoczko JL, Stryer L. New York: W H Freeman; 2002. 8.1.1 Many Enzymes Require Cofactors for Activity http://www.ncbi.nlm.nih.gov/books/NBK22380/ Section 9.2 Making a Fast Reaction Faster: Carbonic Anhydrases http://www.ncbi.nlm.nih.gov/books/NBK22599/

The Medical Biochemistry Pages

Introduction to Vitamins and Minerals http://themedicalbiochemistrypage.org/vitamins.php

Cofactors
What are cofactors? What are coenzymes?
When are coenzymes called prosthetic groups and when are they cosubstrates?

Classification of cofactors
Cofactors

Metals

Small organic molecules

Metalloproteins

Metalassociated proteins

Coenzymes

cosubstrates

Apoenzymes vs. holoenzymes

Vitamin derivatives as cofactors

What are vitamins? Why are they important? What are the two classes of vitamins?

Vitamin C
Ascorbic acid Example: prolyl hydroxylase synthesizes 4hydroxyproline (collagen) An antioxidant

Thiamin (vitamin B1)

Active form: thiamin pyrophosphate, TPP

Pyruvate dehydrogenase complex

Decarboxylation of pyruvate into acetyl CoA by the pyruvate dehydrogenase complex

-ketoglutarate dehydrogenase
Decarboxylation of -ketoglutarate into succinyl CoA by -ketoglutarate dehydrogenase

Riboflavin (vitamin B2)

The precursor for the coenzymes flavin adenine mononucleotide (FMD) and flavin adenine dinucleotide (FAD)

Flavoproteins
Protiens that require FMN or FAD as cofactors Redox reactions FAD and FMN are prosthetic groups

Succinate dehydrogenase
Oxidation of succinate into fumarate by succinate dehydrogenase

Pyruvate dehydrogenase complex

FAD is a prosthetic group for the pyruvate dehydrogenase complex
It does not change in the overall reaction

Niacin (vitamin B3)

Precursor of nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+)
Cofactors for numerous dehydrogenases Cosubstrates

Pantothenic acid (vitamin B5)

Precursor of alanine and pantoic acid

Synthesis of coenzyme A (CoA)

Metabolism of carbohydrate, fats and proteins

Coenzyme A
Coenzyme A transports acetyl groups from one substrate to another
via reactive thioester bond

Pyruvate dehydrogenase complex

Decarboxylation of pyruvate into acetyl CoA by the pyruvate dehydrogenase complex

Citrate synthase
Condensation of acetyl CoA and oxaloacetate into citrate by citrate synthase

Pyridoxal phosphate (vitamin B6)

Pyridoxal, pyridoxamine and pyridoxine are precursors of active form Metabolism of amino acids

Pyridoxine

Pyridoxal

Pyridoxamine

pyridoxal phosphate

Aminotransferases
All aminotransferases contain the prosthetic group pyridoxal phosphate (PLP)

Examples
Aspartate aminotransferase

Alanine aminotransferase

Biotin
Carboxylation reactions

Pyruvate carboxylase
condensation of CO2 to pyruvate forming oxaloacetate by pyruvate carboxylase

Acetyl CoA carboxylase

Carboxylation of acetyl CoA to malonyl CoA by acetyl CoA carboxylase initiating fatty acid synthesis
Biotin is a prosthetic group

Cobalamin (vitamin B12)

Composed of a tetrapyrrol ring structure and a cobalt ion in the center Two significant reactions linking fatty acid metabolism to sugar metabolism by rearranging methylmalonyl CoA to succinyl CoA the formation of methionine from homocysteine by methylation

Folic acid
Reduced within cells to tetrahydrofolate (THF) by dihydrofolate reductase (DHFR), an NADPH-requiring enzyme THF derivatives carry and transfer of one carbon units during biosynthetic reactions, especially of nucleotides

Lipoic acid
Not a dietary requirement in humans
Not a vitamin

A co-factor in pyruvate dehydrogenase and ketoglutarate dehydrogenase

Metals
Metal Zn2+ Zn2+ Enzyme Carbonic anhydrase Carboxypeptidase

Mg2+ Se Mn2+

Hexokinase Glutathione peroxidase Superoxide dismutase

Example