Chapter 7 (part 1) Cofactors

Cofactors are organic or inorganic molecules that are required for the activity of a certain conjugated enzymes Apoenzyme = enzyme (-) cofactor Holoenzyme = enzyme (+) cofactor Inorganic cofactors – essential ions Organic cofactors – coenzymes

Essential Ion Cofactors Activator ions – bind reversibly to enzyme and often participate in substrate binding. Metal ions of metalloenzymes – cations that are tightly bound to enzyme and participate directly in catalysis (Fe, Zn, Cu, Co). Metal activated enzymes – require or are stimulated by addition of metal ions (i.e. Mg 2+, is required by many ATP requiring enzymes)

Metal ions can function as electrophiles in active site Zinc protease (angiotensin converting enzyme)

Coenzymes Cosubstrates- - altered in rxn and regenerated to original structure in subsequent rxn - disassociated from active site - shuttle chemical groups among different enzyme rxns. Prosthetic groups- - remains bound to enzyme - must return to original form Both cosubstrates and prosthetic groups supply reactive groups not present on amino acid side chains

Metabolite coenzymes – synthesized from common metabolites Nucleoside triphosphates – (ATP) can donate phosphates, pyrophosphates, adenosyl grroups S-adenosylmethionine (SAM) – donates methyl groups Nucleotide sugars (uridine diphosphate glucose = UDP-glucose) - transfer sugars in carbohydrate metabolism Coenzymes

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

Vitamins VitaminCoenzyme Ascorbic acid (C)not a coenzyme NiacinNAD(P)+/NAD(P)H Riboflavin (B 2 )FMN & FAD Thiamin (B 1 )Thiamin-pyrophosphate Pyridoxal (B 6 )Pyridoxal phosphateBiotin FolateTetrahydrafolate Cobalamin (B 12 )adenosyl-and methylcobalamin Vitamin ARetinalVitamin K Pantothenate (B 3 )Coenzyme A

Niacin (nicotinic acid) Deficiencies lead to pellagra (dermatitis, diarrhea, dementia) Required in relatively high amounts compared to other vitamins Not true enzyme because can be synthesized from tryptophan in the liver

Nicotinamide Coenzymes

NAD + / NADP + Serve as cofactors in oxidation/reduction reactions Act as co-substrates for dehydrogenases Reduction of NAD + /NADP + and oxidation of NADH/NADPH occurs 2 e- at a time. Function in hydride ion transfer Rxns forming NADH/NADPH are catabolic NADH is coupled with ATP production in mitochondria NADPH is an impt reducing agent in biosynthetic reactions Reduced forms (NADH/NADPH) absorb light at 340 nm, oxidized forms (NAD + /NADP + ) do not

Riboflavin (B2) Water soluble vitamin Severe deficiencies lead to growth retardation, reproductive problems and neural degeneration Meat, dairy products and dark green vegetables, legumes and grains are good sources

FMN/FAD

FAD and FMN can transfer electrons one or two at a time Hydroquinone form Quinone form semiquinone form

Thiamin Thiamin is the first Vitamin discovered (Vital amine = Vitamin) Deficiencies lead to disease called Beriberi (neurological disorders, heart problems, anorexia) Beriberi prevealent in undeveloped countries where polished grains make up the majority of the diet. Associated with alcohol related disorders (Wernickes-Korskofff syndrome – memory loss, unstable walk)

Thiamin pyrophosphate Serves as a cofactor in decarboxylation rxn of keto acids Also functions as a prosthetic group in transketolases (catalyze the transfer of two carbon units in carbohydrate metabolism)

Thiazolium ring is the chemically active part of TPP Ylid = a molecule with opposite charges on adjacent atoms

Pyridoxal

PYRIDOXAL-PHOSPHATE Important in amino acid metabolism Bound to enzyme as a Schiff base thru rxn with lysine PLP functions in transamination, decarboxylation, racemization, isomerization, side-chain elimination rxns involving amino acids

PLP in transamination reaction

PLP in amino acid decarboxylation reaction