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27 General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March © 2003 Thomson Learning, Inc. All rights reserved 27-1 27Chapter 27 Specific Catabolic Pathways: Carbohydrate, Lipid, and Protein Metabolism © 2003 Thomson Learning, Inc. All rights reserved 27-2 27Glycolysis • Glycolysis: a series of 10 enzyme-catalyzed reactions by which glucose is oxidized to two molecules of pyruvate C6 H1 2 O6 Glucos e glycolys is O 2 CH3 CCOO - + 2 H+ Pyruvate • there is net conversion of 2ADP to 2ATP C6 H1 2 O6 + 2 ADP + 2 Pi Glucose © 2003 Thomson Learning, Inc. All rights reserved O 2 CH3 CCOO - + 2 ATP Pyruvate 27-3 27Glycolysis - Rexn 1 • reaction 1: phosphorylation of -D-glucose HO HO CH2 OH O O O + -O-P-O-P-O-AMP OH -D -Glucose OH HO HO - O - O ATP CH 2 OPO3 O 2- OH OH -D -Glucose 6-p hosphate © 2003 Thomson Learning, Inc. All rights reserved hexokinas e 2+ Mg O + - O-P-O-AMP O ADP 27-4 27Glycolysis - Rexn 2 • reaction 2: isomerization of glucose 6-phosphate to fructose 6-phosphate 6 HO HO 6 2- CH2 OPO3 O 2 OH ph os phoglu coisomeras e 1 OH -D-Glu cose 6-phosp hate © 2003 Thomson Learning, Inc. All rights reserved 2- CH2 OPO3 1 CH2 OH O H HO 2 H OH HO H -D -Fru ctos e 6-phosp hate 27-5 27Glycolysis - Rexn 2 • this isomerization is most easily seen by considering the open-chain forms of each monosaccharide; it is one keto-enol tautomerism followed by another 1 CHO H 2 OH HO H H OH H OH CH2 OPO3 2 Glucose 6-p hos phate © 2003 Thomson Learning, Inc. All rights reserved H C OH C OH HO H H OH H OH CH2 OPO3 2(A n ened iol) 1 CH2 OH 2C O HO H H OH H OH CH2 OPO3 2 Fru ctose 6-phosp hate 27-6 27Glycolysis - Rexn 3 • reaction 3: phosphorylation of fructose 6- phosphate 6 CH2 OPO3 2 1 CH2 OH O H HO + ATP H OH HO H -D -Fru ctose 6-phosp hate phosph ofructokin ase Mg 2+ 6 2- CH2 OPO3 1 CH2 OPO3 2 O + ADP H HO H OH HO H -D-Fructose 1,6-bis phosp hate © 2003 Thomson Learning, Inc. All rights reserved 27-7 27Glycolysis - Rexn 4 • reaction 4: cleavage of fructose 1,6-bisphosphate to two triose phosphates CH2 OPO3 2- C=O HO H H al dol ase H OH OH CH2 OPO3 2 - Fructose 1,6-b isph osp hate © 2003 Thomson Learning, Inc. All rights reserved CH2 OPO3 2 C=O CH2 OH CHO H C OH CH2 OPO3 2 - D ih yd roxyacetone p hos phate D -Glyceraldehyde 3-p hosph ate 27-8 27Glycolysis - Rexn 5 • reaction 5: isomerization of triose phosphates • catalyzed by phosphotriose isomerase • reaction involves two successive keto-enol tautomerizations • only the D enantiomer of glyceraldehyde 3-phosphate is formed CH2 OH C= O CHOH C-OH CH2 OPO 3 2 - CH2 OPO 3 2 - Dihydroxyacetone phosphate © 2003 Thomson Learning, Inc. All rights reserved An enediol intermediate CHO H C OH CH2 OPO 3 2 D-Glyceraldehyde 3-phosphate 27-9 27Glycolysis - Rexn 6 • 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 2CH2 OPO3 D -Glyceraldehyde 3-ph os phate © 2003 Thomson Learning, Inc. All rights reserved + + NAD + Pi glyceraldeh yd e 3-p hosphate d ehydrogenase O 2C-OPO3 H C OH + NADH 2CH2 OPO3 1,3-Bis phosp hoglycerate 27-10 27Glycolysis - Rexn 7 • Reaction 7: transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP O 2C-OPO3 + H C OH CH2 OPO3 2 1,3-Bisp hos phoglycerate © 2003 Thomson Learning, Inc. All rights reserved O O-P-O-AMP O- phosp hoglycerate kinas e Mg 2 + AD P COOO O + -O-P-O-P-O-AMP H C OH O O CH2 OPO3 2 3-Ph os phoglycerate ATP 27-11 27Glycolysis - Rexn 8 & 9 • Reaction 8: isomerization of 3-phosphoglycerate to 2-phosphoglycerate phosph oglycerate COOCOOmutas e H C OH H C OPO3 2 CH2 OH CH2 OPO3 22-Ph os phoglycerate 3-Phos phoglycerate • Reaction 9: dehydration of 2-phosphoglycerate COOCOOen olase 22+ H2 O H C OPO3 C OPO 2+ 3 Mg CH2 OH CH2 2-Phosph oglycerate Phosph oen olp yruvate © 2003 Thomson Learning, Inc. All rights reserved 27-12 27Glycolysis - Rexn 10 • Reaction 10: phosphate transfer to ADP - COO O 2C OPO3 + O-P-O-AMP CH2 OPh os phoenolpyruvate © 2003 Thomson Learning, Inc. All rights reserved pyru vate kinas e Mg2 + AD P O O COOC=O + O-P-O-P-O-AMP O- OCH3 A TP Pyruvate 27-13 27Glycolysis • Summing these 10 reactions gives the net equation for glycolysis C6 H1 2 O6 + 2 N A D+ + 2 HPO 4 2 - + 2 A DP Glucos e O 2 CH3 CCOO - + 2 NADH + Pyruvate © 2003 Thomson Learning, Inc. All rights reserved glycolys is 2 ATP + 2 H 2 O + 2 H + 27-14 27Reactions 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 p lants and animals Acetyl CoA 13 Citric acid cycle OH O - 11 anaerob ic conditions CH3 CHCOOCH3 CCOO contracting mu scle Lactate Pyruvate 10 anaerob ic conditions CH3 CH2 OH + CO2 fermentation in yeast Ethanol © 2003 Thomson Learning, Inc. All rights reserved 27-15 27Reactions 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 it © 2003 Thomson Learning, Inc. All rights reserved 27-16 27Pyruvate to Lactate • in vertebrates under anaerobic conditions, the most important pathway for the regeneration of NAD+ is reduction of pyruvate to lactate lactate O dehydrogenase + CH3 CCOO + NA DH + H Pyruvate OH CH3 CHCOO- + NA D+ Lactate • lactate dehydrogenase (LDH) is a tetrameric isoenzyme consisting of H and M subunits; H4 predominates in heart muscle, and M4 in skeletal muscle © 2003 Thomson Learning, Inc. All rights reserved 27-17 27Pyruvate to Lactate • while reduction to lactate allows glycolysis to continue, it increases the concentration of lactate and also of H+ in muscle tissue C6 H1 2 O6 Glucos e lactate fermentation OH 2 CH3 CHCOO- + 2 H+ Lactate • when blood lactate reaches about 0.4 mg/100 mL, muscle tissue becomes almost completely exhausted © 2003 Thomson Learning, Inc. All rights reserved 27-18 27Pyruvate to Ethanol • Yeasts and several other organisms regenerate NAD+ by this two-step pathway • decarboxylation of pyruvate to acetaldehyde pyruvate O decarboxylase + CH3 CCOO + H Pyruvate O CH3 CH + CO 2 Acetaldehyde • reduction of acetaldehyde to ethanol alcohol O dehydrogenase + CH3 CH + N AD H + H Acetaldehyde CH3 CH2 OH + NA D + Ethanol © 2003 Thomson Learning, Inc. All rights reserved 27-19 27Pyruvate 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 oxidative O decarboxylation CH3 CCOO - + NAD+ + CoASH Pyruvate O CH3 CSCoA + CO2 + N ADH Acetyl-CoA © 2003 Thomson Learning, Inc. All rights reserved 27-20 27Energy Yield of Glycolysis Step 1, 3 5 6, 9 12 13 © 2003 Thomson Learning, Inc. All rights reserved Reaction(s) Activation (glucose -> fru ctose 1,6-bisp hosphate ATP prod uced -2 4 Oxidative phosp horylation (2 glyceraldeh yd e 3-phosph ate -> 1,3-bis phosph oglycerate), produces 2N AD + 4 Ph os phate transfer to A DP from 1,3-bisph os phoglycerate and phosph oen olp yruvate 6 Oxidative decarboxylation (2 pyruvate -> acetyl CoA), produces 2N AD + 24 Oxidation to tw o acetyl CoA in th e citric acid cycle etc. TOTAL 36 27-21 27Catabolism of Glycerol • Glycerol enters glycolysis via dihydroxyacetone phosphate CH2 OH ATP CHOH CH2 OH Glycerol © 2003 Thomson Learning, Inc. All rights reserved ADP + NAD CH2 OH CHOH CH2 OPO3 2Glycerol 1-phosph ate NADH CH2 OH C=O CH2 OPO3 2 D ihydroxyacetone phosp hate 27-22 27Fatty 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 (k cal• mol ) (kcal• g -1) C6 H1 2 O6 + 6 O2 Glucose CH3 (CH2 ) 1 4 COOH + 2 3 O2 Palmitic acid © 2003 Thomson Learning, Inc. All rights reserved 6 CO2 + 6 H2 O 686 3.8 1 6 CO2 +1 6 H2 O 2,340 9.3 27-23 27b-Oxidation • b-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 + 2 Pi An acyl CoA © 2003 Thomson Learning, Inc. All rights reserved 27-24 27b-Oxidation • Reaction 2: oxidation of the ,b carbon-carbon single bond to a carbon-carbon double bond acyl-CoA O b dehydrogenase R- CH2 -CH2 - C-SCo A + FAD O An acyl-CoA H C-SCo A + FAD H2 C C R H A trans enoyl-CoA © 2003 Thomson Learning, Inc. All rights reserved 27-25 27b-Oxidation • Reaction 3: hydration of the double bond O enoyl-CoA H C-SCo A hydratas e + C C H2 O R H A trans enoyl-CoA OH R C H O CH2 -C- SCoA An L- b-hydroxyacyl-CoA • Reaction 4: oxidation of the 2alcohol to a ketone OH C H O CH2 -C-SCoA R b-Hyd roxyacyl-CoA © 2003 Thomson Learning, Inc. All rights reserved + NAD+ b-h yd roxyacyl-CoA dehydrogenas e O O R-C-CH2 -C-SCoA + NADH + H+ b-Ketoacyl-CoA 27-26 27b-Oxidation • Reaction 5: cleavage of the carbon chain by a molecule of CoA-SH O O th iolas e 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 © 2003 Thomson Learning, Inc. All rights reserved 27-27 27b-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 O CH3 ( CH2 ) 1 6 C-SCoA + Octadecanoyl-CoA (Stearyl-CoA) 8 CoA-SH + 8 NAD 8 FAD eigh t cycles of b-oxidation O 9 CH3 C-SCoA + A cetyl-CoA 8 NADH 8 FADH2 • b-oxidation of unsaturated fatty acids proceeds in the same way, with an extra step that isomerizes the cis double © 2003 Thomson Learning, Inc. bond to a trans double bond All rights reserved 27-28 27Energy Yield from b-Oxidation • Yield of ATP per mole of stearic acid (C18) Step Chemical Step Happ ens ATP 1 Activation (stearic acid -> stearyl CoA) Once -2 2 Oxidation (acyl CoA -> trans-enoyl CoA) produces FA D H 2 8 times 16 4 Oxidation (hydroxyacyl CoA to ketoacyl CoA ) produ ces N A D H 8 times 24 Oxidation of acetyl CoA 9 times by the common metabolic path w ay, etc. TOTAL 108 © 2003 Thomson Learning, Inc. All rights reserved 146 27-29 27Ketone Bodies • Ketone bodies: acetone, b-hydroxybutyrate, and acetoacetate • 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 • intake high in lipids and low in carbohydrates • diabetes not suitably controlled • starvation © 2003 Thomson Learning, Inc. All rights reserved 27-30 27Ketone Bodies O 2 CH3 C-SCoA Acetyl-CoA HS-CoA O O CH3 CCH2 C-SCoA Acetoacetyl-CoA O NADH OH CH3 -C-CH2 -COOCH3 -CH-CH2 -COOA cetoacetate NAD+ + H+ b-Hyd roxybutyrate CO2 © 2003 Thomson Learning, Inc. All rights reserved O CH3 -C-CH3 Acetone 27-31 27 Protein Catabolism © 2003 Thomson Learning, Inc. All rights reserved 27-32 27Nitrogen of Amino Acids • -NH2 groups move freely by transamination • pyridoxal phosphate (Section18.7B) forms an imine (a C=N group) with the -amino group of an amino acid • rearrangement gives an isomeric imine • hydrolysis of the isomeric imine gives an -ketoacid and pyridoxamine R-CH-COONH2 + O CH E-Pyr P © 2003 Thomson Learning, Inc. All rights reserved R-CH-COO- R-C-COO- N CH N CH2 E-Pyr P E-Pyr P An imine A n isomeric imine R-C-COOO + NH2 CH2 E-Pyr P 27-33 27Nitrogen of Amino Acids • nitrogens to be excreted are collected in glutamate, which is oxidized to -ketoglutarate and NH4+ - COO + + NAD CH-NH3 + H2 O CH2 CH2 COOGlu tamate - COO NADH C=O CH2 + NH4 + CH2 COO-Ketoglutarate • NH4+ then enters the urea cycle © 2003 Thomson Learning, Inc. All rights reserved 27-34 27The Urea Cycle - Overview • Urea cycle: a cyclic pathway that produces urea from CO2 and NH4+ + CO2 + NH4 2 ATP 2 ADP + 2 H2 O + O 2- © 2003 Thomson Learning, Inc. All rights reserved - H3 N-CHCH2 COO Aspartate H2 N-C-OPO3 Carbamoyl p hosphate O H 2 N-C-NH2 Urea COO- COO- H Urea cycle C C - OOC H Fumarate 27-35 27The Urea Cycle - O H 2 N-C-OPO3 NH3 + ( CH2 ) 3 CH-NH3 + - COO Orn ithine 2- + COO H 3 N-CHCH2 COOAs partate NH2 C O NH ( CH2 ) 3 CH-NH3 + COOCitru llin e NH2 COOC N-CHCH2 COO NH ( CH 2 ) 3 CH-NH3 + COOA rgininosu ccinate © 2003 Thomson Learning, Inc. All rights reserved (next s creen ) 27-36 27The Urea Cycle O H2 N -C- NH2 Urea N H3 + ( CH2 ) 3 CH- NH3 + COOOrnithine N H2 C N H2 + NH N H2 COOC N -CHCH2 COO NH ( CH2 ) 3 CH- NH3 + COOArginine COO- H - © 2003 Thomson Learning, Inc. All rights reserved ( CH2 ) 3 C C OOC H Fumarate CH- NH3 + COOArgininosuccinate 27-37 27Amino Acid Catabolism • The breakdown of amino acid carbon skeletons follows two pathways • glucogenic amino acids: ones whose carbon skeletons are degraded to pyruvate or oxaloacetate, both of which may then be converted to glucose by gluconeogenesis • ketogenic amino acids: ones whose carbon skeletons are degraded to acetyl CoA or acetoacetyl CoA, both of which may then be converted to ketone bodies © 2003 Thomson Learning, Inc. All rights reserved 27-38 27Amino Acid Catabolism Glucogenic Aspartate Asparagine Alanine Glycine Serine Threonine Cysteine Glutamate Glutamine Arginine Proline Histidine Valine Methionine © 2003 Thomson Learning, Inc. All rights reserved Ketogenic Leucine Lys ine Glucogenic and Ketogenic Is oleucine Phenylalanine Tryptophan Tyrosine 27-39 27Heme Catabolism • When red blood cells are destroyed • globin is hydrolyzed to amino acids • 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 © 2003 Thomson Learning, Inc. All rights reserved 27-40 27Catabolic Pathways + CO2 + NH4 2 ATP 2 ADP + 2 H2 O + O 2- End Chapter 27 © 2003 Thomson Learning, Inc. All rights reserved - H3 N-CHCH2 COO Aspartate H2 N-C-OPO3 Carbamoyl p hosphate O H 2 N-C-NH2 Urea COO- COO- H Urea cycle C C - OOC H Fumarate 27-41