Chem 109 C Bioorganic Compounds

Fall 2019 HFH1104

Armen Zakarian Office: Chemistry Bldn 2217

http://labs.chem.ucsb.edu/~zakariangroup/courses.html Chapter 23: Coenzymes

Overview and Introduction: • enzymes are biological catalysts • many enzymes are inactive without cofactors

• cofactors are 1) metal ions or 2) coenzymes

• coenzymes - organic molecules, derived from vitamins Chapter 23: Coenzymes

Coenzyme Vitamin Reaction catalyzed NAD+, NADP+ / NADH, oxidation/reduction of niacin, nicotinamide NADPH alcohols oxidation/reduction, FAD / FADH riboflavin (B2) 2 other Thiamine pyrophosphate thiamine (B1) acyl group transfer TPP Lipoic acid /dihydropipoic lipoic acid oxidation/reduction acid Coenzyme A, CoASH pantothenic acid (B5) acyl group transfer

Biotin biotin (B7) carboxylation

Pyridoxal phosphate PLP pyridoxin (B6) 6 amino acid reactions

Coenzyme B12 vitamin B12 isomerization

Tetrahydrofolic acid, THF folic acid one-carbon transfer

Vitamin KH2 vitamin K carboxylation

Vitamin KH2 is not soluble in water see Table 23.1 in Chapter 23 Chapter 23: Coenzymes factors characterizing a coenzyme:

• chemical structure • associated vitamin • type of reaction catalyzed • reaction mechanism • dietary source • associated disease NAD+-NADH, NADP+-NADPH

O O H H vitamin: NH2 NH2 N+ N O O O O O O O NH P P 2 -O HO OH -O HO OH N NH NH O 2 O 2 nicotinamide N N N N O O P N N P N N -O O O -O O O

HO OH HO OH

NAD+ NADH

NAD+ is a catabolic enzyme [NAD+]/[NADH] ~ 1000 : 1

• catalyze redox (oxidation-reduction) reactions • source of nicotinamide: meats, vegetables, peanuts etc. • deficiency disease: pellagra (skin lesions, sensitivity to light etc.) NAD+-NADH, NADP+-NADPH

O H H O vitamin: NH2 NH2 N+ N O O O O O O O NH P P 2 -O HO OH -O HO OH N NH NH O 2 O 2 nicotinamide N N N N O O P N N P N N -O O O -O O O

HO O HO O O P O P - O- O - O- O

NADP+ NADPH

NADP+ is an anabolic enzyme [NADP+]/[NADPH] ~ 1 : 100

• catalyze redox (oxidation-reduction) reactions • source of nicotinamide: meats, vegetables, peanuts etc. • deficiency disease: pellagra (skin lesions, sensitivity to light etc.) FAD-FADH2, FMN-FMNH2

vitamin B2: NH2 NH2 N N N N OH O O N N O O N N H OH P P O P P O O O O O O O H OH O- O- O- O- H OH H OH H OH HO OH HO OH H OH H OH CH2 H OH H OH N N O CH CH 2 2 NH H N N N O N N O O NH NH riboflavin N N H O O

FAD FADH2

• catalyze redox (oxidation-reduction) reactions • source of riboflavin: milk, liver, mushrooms, etc. • deficiency disease: skin inflammation, cracked lips, sensitivity to light… + + NAD , NADP

Oxidation with NAD+ (or NADP+):

OH dehydrogenase O + NAD+ + :B- + NADH + H-B R R' R R'

General mechanism of oxidation:

:B- H-B R H R R' O- R R' R' O O H oxidation of alcohol H O O H H O NH2 NH2 NH2 N+ N+ N R R R + + NAD , NADP

Oxidation with NAD+ (or NADP+), examples:

malate OH O dehydrogenase -OOC + NAD+ + :B- -OOC + NADH + H-B COO- COO-

malate oxaloacetate

• important reaction in the citric acid cycle + + NAD , NADP

Reduction with NADH (or NADPH), a reverse process:

O dehydrogenase OH + NADH + H-B + NAD+ + :B- R R' R R'

General mechanism of reduction:

:B- H-B H R R R' R' O O reduction of carbonyl group H H H O O NH NH2 2 + N N R R

• NADH and NADPH are H¯ donors + + NAD , NADP

Reduction with NADPH (or NADH), examples:

homoserine NH + + O 3 dehydrogenase HO NH3 + NADPH + H-B + NADP+ + :B- COO- COO-

β-aspartate semialdehyde homoserine

• important reaction in an anabolic pathway + + NAD , NADP

Oxidation - a more complex example:

glyceraldehyde-3-phosphate 2- OPO3 O O dehydrogenase O OH + NAD+ + OH + NADH + H+ -O P - OH 2- O 2- OPO3 OPO3

D-glyceraldehyde-3-phosphate D-1,3-diphosphoglycerate

R R' O-

H O

NH2 N+ R + + NAD , NADP glyceraldehyde-3-phosphate 2- OPO3 O O dehydrogenase O OH + NAD+ + OH + NADH + H+ -O P - OH 2- O 2- OPO3 OPO3

D-glyceraldehyde-3-phosphate D-1,3-diphosphoglycerate

O

- B R H B H R substrate H O R S - GAP S H O H NAD+ NAD+

B B- H

H R + S NAD S O NAD+ NADH NADH

+ B B H H O O O R -O P R - OH C P - S - O R O O O S O- O + O product O P NAD - NAD+ -O O + + NAD , NADP

Stereochemistry of enzymatic reactions: enzyme reactions are stereospecific

alcohol H Ha Hb dehydrogenase b + + + NAD + NADHa + H CH3 OH CH3 O

:B- H-B H R R R' R' O O reduction of carbonyl group Ha O Ha Hb O NH NH2 2 + N N R R