Chapter 20 Specific Catabolic Pathways: Carbohydrate, Lipid, and Protein Metabolism

Convergence of Pathways Figure 20.2 Convergence of the specific pathways of carbohydrate, fat, and protein catabolism into the common pathway, which is made up of citric acid cycle and oxidative phosphorylation.

Glycolysis Glycolysis: A series of 10 enzyme-catalyzed reactions by which glucose is oxidized to two molecules of pyruvate. During glycolysis, there is net conversion of 2ADP to 2ATP.

Glycolysis Reaction 1: Phosphorylation of -D-glucose.

Glycolysis Reaction 2: Isomerization of -D-glucose 6-phosphate to -D-fructose 6-phosphate.

Glycolysis This isomerization is most easily seen by considering the open-chain forms of each monosaccharide. It is one keto- enol tautomerism followed by another.

Glycolysis Reaction 3: Phosphorylation of fructose 6-phosphate.

Glycolysis Reaction 4: Cleavage of fructose 1,6-bisphosphate to two triose phosphates.

Glycolysis Reaction 5: Isomerization of triose phosphates. Catalyzed by phosphotriose isomerase. The mechanism involves two successive keto-enol tautomerizations. Only the D enantiomer of glyceraldehyde 3-phosphate is formed.

Glycolysis Reaction 6: Oxidation of the -CHO group of D-glyceraldehyde 3-phosphate. The product contains a phosphate ester and a high- energy mixed carboxylic-phosphoric anhydride.

Glycolysis Reaction 7: Transfer of a phosphate group from 1,3- bisphosphoglycerate to ADP.

Glycolysis Reaction 8: Isomerization of 3-phosphoglycerate to 2-phosphoglycerate. Reaction 9: Dehydration of 2-phosphoglycerate.

Glycolysis Reaction 10: Phosphate transfer to ADP.

Glycolysis Summing these 10 reactions gives the net equation for glycolysis:

Reactions of Pyruvate Pyruvate is most commonly metabolized in one of three ways, depending on the type of organism and the presence or absence of O2.

Reactions of Pyruvate A key to understanding the biochemical logic behind two of these reactions of pyruvate 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 reoxidize.

Pyruvate to Lactate In vertebrates under anaerobic conditions, the most important pathway for the regeneration of NAD+ is reduction of pyruvate to lactate. Pyruvate, the oxidizing agent, is reduced to lactate. Lactate dehydrogenase (LDH) is a tetrameric isoenzyme consisting of H and M subunits; H4 predominates in heart muscle, M4 in skeletal muscle.

Pyruvate to Lactate While reduction to lactate allows glycolysis to continue, it increases the concentration of lactate and also of H+ in muscle tissue. 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. Acetaldehyde is then reduced to ethanol. NADH is the reducing agent. Acetaldehyde is reduced and is the oxidizing agent in this redox reaction.

Pyruvate to Acetyl-CoA Under aerobic conditions, pyruvate undergoes oxidative decarboxylation. The carboxylate group is converted to CO2. The remaining two carbons are converted to the acetyl group of acetyl CoA. This reaction provides entrance to the citric acid cycle.

Pentose Phosphate Pathway Figure 20.5 Simplified schematic representation of the pentose phosphate pathway, also called a shunt.

Energy Yield in Glycolysis

Catabolism of Glycerol Glycerol enters glycolysis via dihydroxyacetone phosphate.

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

-Oxidation -Oxidation: A series of five enzyme-catalyzed reactions that cleaves carbon atoms two at a time from the carboxyl end of a fatty acid. Reaction 1: The fatty acid is activated by conversion to an acyl CoA. Activation is equivalent to the hydrolysis of two high-energy phosphate anhydrides.

-Oxidation Reaction 2: Oxidation by FAD of the , carbon-carbon single bond to a carbon-carbon double bond.

-Oxidation Reaction 3: Hydration of the C=C double bond to give a 2° alcohol. Reaction 4: Oxidation of the 2°alcohol to a ketone.

-Oxidation Reaction 5: Cleavage of the carbon chain by a molecule of CoA-SH.

-Oxidation This cycle of reactions is then repeated on the shortened fatty acyl chain and continues until the entire fatty acid chain is degraded to acetyl CoA. b-Oxidation of unsaturated fatty acids proceeds in the same way, with an extra step that isomerizes the cis double bond to a trans double bond.

Energy Yield on -Oxidation Yield of ATP per mole of stearic acid (C18).

Ketone Bodies Ketone bodies: Acetone, -hydroxybutyrate, and acetoacetate; Are formed principally in liver mitochondria. Can be used as a fuel in most tissues and organs. Formation occurs when the amount of acetyl CoA produced is excessive compared to the amount of oxaloacetate available to react with it and take it into the TCA; for example: Dietary intake is high in lipids and low in carbohydrates. Diabetes is not suitably controlled. Starvation.

Ketone Bodies

Protein Catabolism Figure 20.7 Overview of pathways in protein catabolism.

Nitrogen of Amino Acids -NH2 groups move freely by transamination Pyridoxal phosphate forms an imine (a C=N group) with the -amino group of an amino acid. Rearrangement of the imine gives an isomeric imine. Hydrolysis of the isomeric imine gives an -ketoacid and pyridoxamine. Pyridoxamine then transfers the -NH2 group to another a-ketoacid.

Nitrogen of Amino Acids Nitrogens to be excreted are collected in glutamate, which is oxidized to a-ketoglutarate and NH4+. The conversion of glutamate to -ketoglutarate is an example of oxidative deamination. NH4+ then enters the urea cycle.

Urea Cycle—An Overview Urea cycle: A cyclic pathway that produces urea from CO2 and NH4+.

Amino Acid Catabolism The breakdown of amino acid carbon skeletons follows two pathways. Glucogenic amino acids: Those whose carbon skeletons are degraded to pyruvate or oxaloacetate, both of which may then be converted to glucose by gluconeogenesis. Ketogenic amino acids: Those whose carbon skeletons are degraded to acetyl CoA or acetoacetyl CoA, both of which may then be converted to ketone bodies.

Amino Acid Catabolism Figure 20.9 Catabolism of the carbon skeletons of amino acids.

Amino Acid Catabolism

Heme Catabolism When red blood cells are destroyed: Globin is hydrolyzed to amino acids to be reused. Iron is preserved in ferritin, an iron-carrying protein, and reused. Heme is converted to bilirubin. Bilirubin enters the liver via the bloodstream and is then transferred to the gallbladder where it is stored in the bile and finally excreted in the feces.

Heme Catabolism Figure 20.10 Heme degradation from heme to biliverdin to bilirubin.

Heme Catabolism Figure 20.11 A summary of catabolism showing the role of the common metabolic pathway.