Chapter 20 Specific Catabolic Pathways: Carbohydrate, Lipid, and Protein Metabolism What is the General Outline of Catabolic Pathway? Carbohydrates are broken down by enzymes and stomach acid to produce monosaccharides Lipids are hydrolyzed by lipase to glycerol and fatty acids or smaller units Proteins are hydrolyzed by HCl and digestive enzyme in the stomach and intestines to produce their constituent amino acids 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. C6 H12 O 6 Glucose glycolysis O 2CH3 CCOO- + 2H+ Pyruvate • During glycolysis, there is net conversion of 2ADP to 2ATP. C6 H12 O 6 + 2ADP Glucose + 2Pi O 2CH3 CCOO- + Pyruvate 2ATP Glycolysis • Reaction 1: Phosphorylation of -D-glucose. HO HO CH2 OH O O O + -O-P-O-P-O-AMP OH O- Oa-D-Glucose OH ATP HO HO CH2 OPO3 2O hexokinase Mg2+ O + -O-P-O-AMP O- OH OH a-D-Glucose 6-phosphate ADP Glycolysis • Reaction 2: Isomerization of -D-glucose 6-phosphate to -D-fructose 6-phosphate. 6 CH2 OPO3 21 phosphohexose CH2OH O HO isomerase H HO 2 HO 2 1 H OH OH OH HO H a-D-Glucose 6-phosphate a-D-Fructose 6-phosphate 6 CH2 OPO3 O 2- Glycolysis This isomerization is most easily seen by considering the open-chain forms of each monosaccharide. It is one ketoenol tautomerism followed by another. 1 CHO H 2 OH HO H H OH H OH CH2 OPO3 2Glucose 6-phosphate H C OH C OH HO H H OH H OH CH2 OPO3 2(An enediol) CH2 OH 2C O HO H H OH H OH CH2 OPO3 2Fructose 6-phosphate 1 Glycolysis • Reaction 3: Phosphorylation of fructose 6-phosphate. 6 CH2 OPO3 21 CH2 OH O H HO + ATP H OH HO H a-D-Fructose 6-phosphate phosphofructokinase Mg2+ 6 CH2 OPO3 21 CH2 OPO3 2O + ADP H HO H OH HO H a-D-Fructose 1,6-bisphosphate Glycolysis • Reaction 4: Cleavage of fructose 1,6-bisphosphate to two triose phosphates. 2- CH2OPO3 2Dihydroxyacetone C=O phosphate CH2OH CH2 OPO 3 C=O aldolase HO H H OH CHO H OH D-Glyceraldehyde H C OH 3-phosphate CH2 OPO 3 22CH2OPO3 Fructose 1,6-bisphosphate 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. CH2 OH C=O 2- CH2 OPO 3 Dihydroxyacetone phosphate CHO H C OH 2CH2 OPO3 D-Glyceraldehyde 3-phosphate Glycolysis Reaction 6: Oxidation of the -CHO group of D-glyceraldehyde 3-phosphate. • The product contains a phosphate ester and a highenergy mixed carboxylic-phosphoric anhydride. CHO H C OH CH2 OPO3 2D-Glyceraldehyde 3-phosphate glyceraldehyde 3-phosphate + NAD+ + Pi dehydrogenase O 2C-OPO3 H C OH + NADH CH2 OPO3 21,3-Bisphosphoglycerate Glycolysis Reaction 7: Transfer of a phosphate group from 1,3bisphosphoglycerate to ADP. O C-OPO3 2+ H C OH CH2 OPO3 21,3-Bisphosphoglycerate O O-P-O-AMP O- phosphoglycerate kinase Mg 2+ ADP O O COO + -O-P-O-P-O-AMP H C OH 2O O CH2 OPO3 3-Phosphoglycerate ATP Glycolysis Reaction 8: Isomerization of 3-phosphoglycerate to 2-phosphoglycerate. Reaction 9: Dehydration of 2-phosphoglycerate. Glycolysis Reaction 10: Phosphate transfer to ADP. COO O C OPO3 2- + -O-P-O-AMP CH2 O Phosphoenolpyruvate pyruvate kinase Mg2+ ADP O O COOC=O + -O-P-O-P-O-AMP CH3 O O Pyruvate ATP Glycolysis Summing these 10 reactions gives the net equation for glycolysis: C6 H12 O6 + 2NAD+ + 2HPO4 2- + 2ADP Glucose O 2CH3CCOOPyruvate glycolysis + 2NADH + 2ATP + 2H2 O + 2H+ 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. 12 aerobic conditions plants and animals Acetyl CoA 13 Citric acid cycle OH O 11 anaerobic conditions CH CHCOOCH3 CCOO 3 contracting muscle Lactate Pyruvate 10 anaerobic conditions CH3CH2 OH + CO2 fermentation in yeast Ethanol 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 O dehydrogenase CH3 CCOO- + NADH + H+ Pyruvate OH + CH3 CHCOO + NAD 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. C6H12 O6 Glucose lactate fermentation OH 2CH3 CHCOO - + 2H+ Lactate • 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. O - + CH3 CCOO + H Pyruvate pyruvate decarboxylase O CH3 CH + CO 2 Acetaldehyde • Acetaldehyde is then reduced to ethanol. NADH is the reducing agent. Acetaldehyde is reduced and is the oxidizing agent in this redox reaction. O CH3 CH + NADH + H+ Acetaldehyde alcohol dehydrogenase CH3 CH2 OH + NAD+ Ethanol 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. oxidative O CH3 CCOO - + NAD+ + CoASH decarboxylation Pyruvate O CH3 CSCoA + CO2 + NADH Acetyl-CoA Pentose Phosphate Pathway • Figure 20.5 Simplified schematic representation of the pentose phosphate pathway, also called a shunt. Energy Yield in Glycolysis Step 1, 2, 3 Reaction(s) Activation (glucose fructose 1,6-bisphosphate 5 Phosphorylation 4 2 (glyceraldehyde 3-phosphate 1,3-bisphosphoglycerate), produces 2(NAD+ + H+ ) in cytosol 4 Phosphate transfer to ADP from 1,3-bisphosphoglycerate and phosphoenolpyruvate Oxidative decarboxylation 6 2 (pyruvate acetyl CoA), produces 2(NAD+ + H+) Oxidation to two acetyl CoA 24 in the citric acid cycle etc. TOTAL 36 6, 9 12 13 ATP produced -2 Catabolism of Glycerol • Glycerol enters glycolysis via dihydroxyacetone phosphate. CH2 OH CHOH CH2OH Glycerol ATP ADP CH2 OH CHOH + NAD CH2 OPO3 2Glycerol 1-phosphate NADH CH2 OH C=O CH2 OPO 32Dihydroxyacetone 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. Energy Energy -1 (kcal•mol ) (kcal•g-1 ) C6 H12 O6 + 6O 2 Glucose CH3(CH2)14 COOH + 23O2 Palmitic acid 6CO 2 + 6H2O 686 3.8 16CO2 +16H2 O 2,340 9.3 -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. O R-CH2 -CH2 -C-OH + ATP + CoA-SH A fatty acid O R-CH2 -CH2 -C-SCoA + AMP + 2Pi An acyl CoA -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. O O thiolase R-C-CH2 -C-SCoA + CoA-SH b-Ketoacyl-CoA Coenzyme A O O R-C-SCoA + CH3 C-SCoA An acyl-CoA Acetyl-CoA -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. O CH3(CH2)16 C-SCoA + Octadecanoyl-CoA (Stearyl-CoA) 8CoA-SH 8NAD+ 8FAD eight cycles of b-oxidation O 9CH3 C-SCoA + Acetyl-CoA 8NADH 8FADH2 • -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). Step Chemical Step Happens ATP 1 Activation (stearic acid -> stearyl CoA) Once -2 2 Oxidation (acyl CoA —> trans-enoyl CoA) produces FADH2 8 times 16 4 Oxidation (hydroxyacyl CoA to ketoacyl 8 times 24 Oxidation of acetyl CoA 9 times by the common metabolic pathway, etc. TOTAL 108 CoA) produces NADH +H+ 146 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 HS-CoA O O O 2CH3 C-SCoA CH3 CCH2 C-SCoA Acetyl-CoA Acetoacetyl-CoA O NADH OH CH3 -C-CH2-COO CH3 -CH-CH2 -COOAcetoacetate NAD+ + H+ b-Hydroxybutyrate CO 2 O CH3 -C-CH3 Acetone 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 -ketoacid. R-CH-COONH2 + O CH E-Pyr P R-CH-COO -H2 O N CH E-Pyr P An imine R-C-COO R-C-COO +H2 O O N + CH2 NH2 E-Pyr P CH2 An isomeric E-Pyr P imine Nitrogen of Amino Acids Nitrogens to be excreted are collected in glutamate, which is oxidized to -ketoglutarate and NH4+. • The conversion of glutamate to -ketoglutarate is an example of oxidative deamination. COO+ + NAD CH-NH3 + H2 O CH2 CH2 COO Glutamate COONADH C=O + CH2 + NH4 CH2 COO a-Ketoglutarate • NH4+ then enters the urea cycle. Urea Cycle—An Overview Urea cycle: A cyclic pathway that produces urea from CO2 and NH4+. CO2 + NH4 + 2ATP 2ADP + 2H2 O O 2H2 N-C-OPO3 Carbamoyl phosphate O H2 N-C-NH2 Urea Urea cycle - + COO H3 N-CHCH2 COO Aspartate COO- H - C C OOC H Fumarate Urea Cycle - + O H2 N-C-OPO 32NH3 + (CH2 )3 CH-NH3 + COO Ornithine Citrulline - H3 N-CHCH2 COO NH2 C O NH (CH2 )3 CH-NH3 COO- COO Aspartate + NH2 COOC N-CHCH2 COO NH (CH2)3 CH-NH3 + COOArgininosuccinate (nex t screen) Urea Cycle O NH3 + (CH2 )3 CH-NH3 + COO Ornithine H2 N-C-NH2 Urea NH2 C NH2 + NH (CH2 )3 CH-NH3 + COO Arginine - NH2 COOC N-CHCH2 COONH (CH2 )3 COO- H C C OOC H Fumarate + CH-NH3 COO Argininosuccinate 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 Hereditary Defects in Amino acid Catabolism: PKU Occurs in the absence of the enzyme phenylalanine hydroxylase If the enzyme is defective, phenylalanine is convert to phenylpyruvate ( -ketoacid) instead of tyrosine ◦ Inhibits the conversion of pyruvate to acetyl CoA, depriving the cells of energy via the common catabolic pathway ◦ Results in mental retardation or PKU (Phenylketonuria) Prevention: restricting the intake of phenylalanine in diet and artificial sweetener aspartate 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. The color change observed in bruises: Black and blue are due to the congealed blood, green to the biliverdin and yellow to the bilirubin Heme Catabolism Figure 20.11 A summary of catabolism showing the role of the common metabolic pathway.
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