OrganicChemistry William H. Brown & Christopher S. Foote

The Organic Chemistry of Metabolism Chapter 29

Introduction  We have now studied the typical reactions of the major classes of organic compounds, and the structure and reactions of carbohydrates and lipids  Now let us apply this background to the study of the organic chemistry of metabolism  We study two key metabolic pathways  -oxidation of fatty acids glycolysis

Five Key Participants  Five of the compounds participating in these and a great many other metabolic pathways: ATPADPAMPATP, ADP, and AMP are universal carriers of phosphate groups NAD + /NADHFAD/FADH 2NAD + /NADH and FAD/FADH 2 are coenzymes involved in the oxidation/reduction of metabolic intermediates Coenzyme:  Coenzyme: a low-molecular weight, nonprotein molecule or ion that binds reversibly to an enzyme, functions as a second substrate, and is regenerated by further reaction

Adenosine Triphosphate  ATP is the most important compound involved in the transfer of phosphate groups

Adenosine Triphosphate hydrolysis of the terminal phosphate of ATP gives ADP and phosphate in glycolysis, the phosphate acceptors are -OH groups of glucose and fructose

Nicotinamide adenine dinucleotide a biological oxidizing agent

NAD + /NADH  NAD + is a two-electron oxidizing agent, and is reduced to NADH

NAD + /NADH NAD + is involved in a variety of enzyme-catalyzed oxidation/reduction reactions; we deal with two of these in this chapter

NAD + /NADH

FAD/FADH 2

FAD/FADH 2  FAD participates in several types of enzyme- catalyzed oxidation/reduction reactions our concern is its participation in the oxidation of a C- C bond in a fatty acid hydrocarbon chain to a C=C bond as shown in these balanced half-reactions

FAD oxidation of C-C

Fatty Acids and Energy  Fatty acids in triglycerides are the principle storage form of energy for most organisms carbon chains are in a highly reduced form the energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate

Oxidation of Fatty Acids  There are two major stages in the oxidation of fatty acids activation of the free fatty acid in the cytoplasm and its transport across the inner mitochondrial membrane  -oxidation   -Oxidation:   -Oxidation: a series of four enzyme-catalyzed reactions that cleaves carbon atoms two at a time, from the carboxyl end of a fatty acids

Activation of Fatty Acids activation begins in the cytoplasm with formation of a thioester between the carboxyl group of the fatty acid and the sulfhydryl group of coenzyme A formation of the acyl-CoA derivative is coupled with the hydrolysis of ATP to AMP and pyrophosphate

 -Oxidation Reaction 1:Reaction 1: stereospecific oxidation of a carbon- carbon single bond  to the carbonyl group Reaction 2:Reaction 2: regiospecific and stereospecific hydration of the carbon-carbon double bond; only the R- enantiomer is formed

 -Oxidation Reaction 3:Reaction 3: oxidation of the  -hydroxyl group Reaction 4:Reaction 4: cleavage of the carbon chain by a reverse Claisen condensation

 -Oxidation mechanism of the reverse Claisen condensation

 -Oxidation this series of reactions is then repeated on the shortened fatty acyl chain and continues until the entire fatty acid chain is degraded to acetyl-CoA

Glycolysis  Glycolysis:  Glycolysis: from the Greek, glyko, sweet, and lysis, splitting a series of 10 enzyme-catalyzed reactions by which glucose is oxidized to two molecules of pyruvate

Glycolysis - Rexn 1 phosphorylation of  -D-glucose

Glycolysis - Rexn 2 isomerization of glucose 6-phosphate to fructose 6- phosphate

Glycolysis - Rexn 2 this isomerization is most easily seen by considering the open-chain forms of each monosaccharide

Glycolysis - Rexn 3 phosphorylation of fructose 6-phosphate

Glycolysis - Rexn 4 cleavage of fructose 6-phosphate to two triose phosphates

Glycolysis - Rexn 4 reaction 4 is a reverse aldol reaction a key intermediate is an imine formed by the C=O group of fructose 1,6-bisphosphate and an -NH 2 group of the enzyme catalyzing this reaction

Glycolysis - Rexn 4 reverse aldol reaction gives two three-carbon fragments, one as an imine

Glycolysis - Rexn 4 hydrolysis of the imine gives dihydroxyacetone phosphate and regenerates the -NH 2 group of the enzyme

Glycolysis - Rexn 5 isomerization of triose phosphates

Glycolysis - Rexn 6 oxidation of the -CHO group of glyceraldehyde 3- phosphate the -CHO group is oxidized to a carboxyl group which is in turn converted to a carboxylic-phosphoric mixed anhydride the oxidizing agent is NAD +, which is reduced to NADH

Glycolysis - Rexn 6 We divide this reaction into three stages stage 1: formation of a thiohemiacetal stage 2: oxidation of the thiohemiacetal by NAD +

Glycolysis - Rexn 6 stage 3: conversion of the thioester to a mixed anhydride

Glycolysis - Rexn 7 transfer of a phosphate group from 1,3- bisphosphoglycerate to ADP

Glycolysis - Rexn 8 isomerization of 3-phosphoglycerate to 2- phosphoglycerate

Glycolysis - Rexn 9  dehydration of 2-phosphoglycerate

Glycolysis - Rexn 10 phosphate transfer to ADP

Glycolysis Summing these 10 reactions gives the net equation for glycolysis

Fates of Pyruvate  Pyruvate does not accumulate in cells, but rather undergoes one of three enzyme-catalyzed reactions, depending of the type of cell and its state of oxygenation reduction to lactate reduction to ethanol oxidation and decarboxylation to acetyl-CoA  A key to understanding the biochemical logic behind two of these fates is to recognize that glycolysis needs a continuing supply of NAD + if no oxygen is present to reoxidize NADH to NAD +, then another way must be found to do it

Lactate Fermentation in vertebrates under anaerobic conditions, the most important pathway for the regeneration of NAD + is reduction of pyruvate to lactate

Pyruvate to Lactate while lactate fermentation does allow glycolysis to continue, it increases the concentration of lactate and also of H + in muscle tissue, as seen in this balanced half-reaction when blood lactate reaches about 0.4 mg/100 mL, muscle tissue becomes almost completely exhausted

Pyruvate to Ethanol  Yeasts and several other organisms regenerate NAD + by this two step pathway decarboxylation of pyruvate to acetaldehyde reduction of acetaldehyde to ethanol

Pyruvate to Acetyl-CoA  Under aerobic conditions pyruvate undergoes oxidative decarboxylation the carboxylate group is converted to CO 2 the remaining two carbons are converted to the acetyl group of acetyl-CoA

Pyruvate to Acetyl-CoA  Oxidative decarboxylation of pyruvate to acetyl- CoA is considerably more complex than the previous equation suggests  In addition to NAD + (from the vitamin niacin) and coenzyme A (from the vitamin pantothenic acid), it also requires FAD (from the vitamin riboflavin) pyridoxal phosphate (from the vitamin pyridoxine) lipoic acid

Pyruvate to Acetyl-CoA

Prob Describe the type of reaction involved in this biochemical synthesis of  -hydroxybutyrate.

The Organic Chemistry of Metabolism End Chapter 29