27 27-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e Bettelheim, Brown, and March.
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2727
27-1© 2003 Thomson Learning, Inc.All rights reserved
General, Organic, and General, Organic, and Biochemistry, 7eBiochemistry, 7e
Bettelheim,Bettelheim,
Brown, and MarchBrown, and March
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27-2© 2003 Thomson Learning, Inc.All rights reserved
Chapter 27Chapter 27
Specific Catabolic Pathways:Specific Catabolic Pathways:
Carbohydrate, Lipid, Carbohydrate, Lipid,
and Protein Metabolismand Protein Metabolism
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GlycolysisGlycolysis• GlycolysisGlycolysis:: a series of 10 enzyme-catalyzed
reactions by which glucose is oxidized to two molecules of pyruvate
• there is net conversion of 2ADP to 2ATP
C6H12O6Glucose
glycolysis2CH3CCOO-
Pyruvate
+ 2H+O
C6H12O6 + 2ADP + 2Pi 2CH3CCOO- + 2ATP
O
Glucose Pyruvate
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Glycolysis - Rexn 1Glycolysis - Rexn 1• reaction 1reaction 1:: phosphorylation of -D-glucose
HO
OHOH
HOCH2OH
O
O-
-O-P-O-P-O-AMP
O-
O O
Mg2+
OHOH
HOHO
CH2OPO32-
O-O-P-O-AMP
O
O-
ATP
ADP
-D-Glucose
+
+hexokinase
-D-Glucose 6-phosphate
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Glycolysis - Rexn 2Glycolysis - Rexn 2• reaction 2:reaction 2: isomerization of glucose 6-phosphate
to fructose 6-phosphate
O
OHOH
HOHO
CH2OPO32-
HO
CH2OPO32-
CH2OHO
OH
HH
HO
H
2
1
-D-Glucose 6-phosphate -D-Fructose 6-phosphate
phosphogluco- isomerase
6
12
6
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Glycolysis - Rexn 2Glycolysis - 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
CHO
CH2OPO32-
OHHHHOOHHOHH
C
CH2OPO32-
OHHHOOHHOHH
CH OHC
CH2OPO32-
OHHOOHHOHH
CH2OH
Fructose 6-phosphateGlucose 6-phosphate (An enediol)
2
1 1
2
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Glycolysis - Rexn 3Glycolysis - Rexn 3• reaction 3:reaction 3: phosphorylation of fructose 6-
phosphate
HO
CH2OPO32-
CH2OHO
OH
HH
HO
H
ATPMg2+
HO
CH2OPO32-
CH2OPO32-
O
OHH
HHO
H
ADP
1
-D-Fructose 6-phosphate
6
+
phospho-fructokinase
1
-D-Fructose 1,6-bisphosphate
6
+
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Glycolysis - Rexn 4Glycolysis - Rexn 4• reaction 4:reaction 4: cleavage of fructose 1,6-bisphosphate
to two triose phosphates
H
C=O
CH2OPO32-
HOH
CH2OPO32-
OHH
HO
CH2OPO32-
C
CHO
H OH
C=O
CH2OPO32-
CH2OHaldolase
Fructose 1,6-bisphosphate
D-Glyceraldehyde3-phosphate
Dihydroxyacetonephosphate
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Glycolysis - Rexn 5Glycolysis - Rexn 5• reaction 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
C=O
CH2OPO32-
CH2OH
CH2OPO32-
CCHO
H OH
D-Glyceraldehyde3-phosphate
Dihydroxyacetonephosphate
C-OHCHOH
CH2OPO32-
An enediolintermediate
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Glycolysis - Rexn 6Glycolysis - Rexn 6• Reaction 6Reaction 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
CH2OPO32-
CCHO
H OH NAD+
CCH2OPO3
2-
C-OPO32-
OHH
O
NADH
1,3-Bisphospho-glycerate
D-Glyceraldehyde3-phosphate
+ + Pi
+
glyceraldehyde3-phosphate
dehydrogenase
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Glycolysis - Rexn 7Glycolysis - Rexn 7• Reaction 7: Reaction 7: transfer of a phosphate group from
1,3-bisphosphoglycerate to ADP
CCH2OPO3
2-
C-OPO32-
OHH
O
-O-P-O-AMPO
O-
CCH2OPO3
2-
COO-
OHH
ADP
Mg2+
O
O-
-O-P-O-P-O-AMPO
O-
ATP
+
1,3-Bisphospho-glycerate
+
3-Phosphoglycerate
phospho-glycerate kinase
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Glycolysis - Rexn 8 & 9Glycolysis - Rexn 8 & 9• Reaction 8: Reaction 8: isomerization of 3-phosphoglycerate
to 2-phosphoglycerate
• Reaction 9: Reaction 9: dehydration of 2-phosphoglycerate
C
CH2OPO32-
COO-
OHH CCH2OH
COO-
OPO32-H
3-Phosphoglycerate 2-Phosphoglycerate
phosphoglycerate mutase
CCH2OH
COO-
OPO32-H
Mg2+ CCH2
COO-
OPO32- H2O
2-Phosphoglycerate Phosphoenolpyruvate
+enolase
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Glycolysis - Rexn 10Glycolysis - Rexn 10• Reaction 10Reaction 10: phosphate transfer to ADP
CCH2
COO-
OPO32- -O-P-O-AMP
O-
O
C=OCH3
COO-
ADP
Mg2+
-O-P-O-P-O-AMPO-O-
O O
ATP
Phosphoenol- pyruvate
+
+
Pyruvate
pyruvate kinase
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GlycolysisGlycolysis• Summing these 10 reactions gives the net
equation for glycolysis
C6H12O6 + 2NAD+ + 2HPO42- + 2ADP
Glucose
glycolysis
2CH3CCOO-O
Pyruvate+ 2NADH + 2ATP + 2H2O + 2H+
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Reactions of PyruvateReactions 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
CH3CCOO-O
CH3CH2OH
CH3CHCOO-OH
+ CO2
Pyruvate
Ethanol
Lactate
anaerobic conditions
aerobic conditionsplants and animals
contracting muscle
anaerobic conditionsfermentation in yeast
Acetyl CoA Citric acid cycle
10
12
11
13
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Reactions of PyruvateReactions 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
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Pyruvate to LactatePyruvate to Lactate• in vertebrates under anaerobic conditions, the most
important pathway for the regeneration of NAD+ is reduction of pyruvate to lactate
• lactate dehydrogenase (LDH) is a tetrameric isoenzyme consisting of H and M subunits; H4 predominates in heart muscle, and M4 in skeletal muscle
CH3CCOO- + NADH + H+O
Pyruvate
CH3CHCOO- + NAD+OH
Lactate
lactatedehydrogenase
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Pyruvate to LactatePyruvate 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
C6H12O6
Glucose
2CH3CHCOO- + 2H+OH
Lactate
lactatefermentation
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Pyruvate to EthanolPyruvate 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
CH3CH + CO2
O
Acetaldehyde
pyruvatedecarboxylase
CH3CCOO- + H+O
CH3CH + NADH + H+O
Acetaldehyde
alcoholdehydrogenase
CH3CH2OH + NAD+
Ethanol
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Pyruvate to Acetyl-CoAPyruvate 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
Pyruvate
CH3CSCoA + CO2 + NADHO
Acetyl-CoA
oxidativedecarboxylation
CH3CCOO- + NAD+ + CoASHO
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Energy Yield of GlycolysisEnergy Yield of Glycolysis1, 3
5
6, 9
12
13
Reaction(s)Activation (glucose ->fructose 1,6-bisphosphate
Oxidative phosphorylation(2 glyceraldehyde 3-phosphate ->1,3-bisphosphoglycerate), produces 2NAD+
Phosphate transfer to ADPfrom 1,3-bisphosphoglycerateand phosphoenolpyruvate
Oxidative decarboxylation(2 pyruvate -> acetyl CoA), produces 2NAD+
Oxidation to two acetyl CoAin the citric acid cycle etc.
ATP produced
-2
4
4
6
24
36TOTAL
Step
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Catabolism of GlycerolCatabolism of Glycerol• Glycerol enters glycolysis via dihydroxyacetone
phosphate
CH
CH2OH
CH2OHOH
ATP ADPCH
CH2OPO32-
CH2OHOH
NAD+ NADHC=OCH2OH
CH2OPO32-
Glycerol Glycerol1-phosphate
Dihydroxyacetonephosphate
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Fatty Acids and EnergyFatty 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
C6H12O6 + 6O2
CH3(CH2)14COOH + 23O2
6CO2 + 6H2O
16CO2 +16H2OPalmitic acid
Glucose
Energy(kcal•mol-1)
Energy(kcal•g-1)
686 3.8
2,340 9.3
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-Oxidation-Oxidation• -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: 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
R-CH2-CH2-C-OHO
ATP CoA-SH
R-CH2-CH2-C-SCoAO
AMP 2Pi
+ +
+ +
A fatty acid
An acyl CoA
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-Oxidation-Oxidation• Reaction 2: Reaction 2: oxidation of the , carbon-carbon single
bond to a carbon-carbon double bond
R-CH2-CH2-C-SCoAO
An acyl-CoA
+FADO
HC C
C-SCoA
R H
+ FADH2
A trans enoyl-CoA
acyl-CoA dehydrogenase
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-Oxidation-Oxidation• Reaction 3: Reaction 3: hydration of the double bond
• Reaction 4: Reaction 4: oxidation of the alcohol to a ketone
+ H2O
An L--hydroxyacyl-CoA
C
OH
CH2-C-SCoARH
Oenoyl-CoAhydrataseH
C CC-SCoA
R HA trans enoyl-CoA
O
C
OH
CH2-C-SCoAHR
ONAD+
R-C-CH2-C-SCoAO O
NADH H+
-Hydroxyacyl-CoA
-Ketoacyl-CoA
+
-hydroxyacyl-CoAdehydrogenase
+
+
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27-27© 2003 Thomson Learning, Inc.All rights reserved
-Oxidation-Oxidation• Reaction 5:Reaction 5: cleavage of the carbon chain by a molecule
of CoA-SH
R-C-CH2-C-SCoA
OO
CoA-SH
R-C-SCoA
O O
CH3C-SCoA
-Ketoacyl-CoA
+
Coenzyme A
+
An acyl-CoA Acetyl-CoA
thiolase
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27-28© 2003 Thomson Learning, Inc.All rights reserved
-Oxidation-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
• -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
CH3(CH2)16C-SCoAO
8NAD+8CoA-SH
9CH3C-SCoAO
8FAD
8NADH8FADH2
Octadecanoyl-CoA(Stearyl-CoA)
+
+Acetyl-CoA
eight cycles of -oxidation
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Energy Yield from Energy Yield from -Oxidation-Oxidation • Yield of ATP per mole of stearic acid (C18)
ATPStep Chemical Step Happens
1
2
4
Activation (stearic acid -> stearyl CoA)
Oxidation (acyl CoA ->trans-enoyl CoA)produces FADH2
Oxidation (hydroxy-acyl CoA to ketoacylCoA) produces NADH
Oxidation of acetyl CoAby the common metabolicpathway, etc.
Once
8 times
8 times
9 times
-2
16
24
108
TOTAL 146
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Ketone BodiesKetone Bodies• Ketone bodiesKetone bodies: acetone, -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
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Ketone BodiesKetone Bodies
CH3-CH-CH2-COO-OH
CH3CCH2C-SCoA
O O
NADH
HS-CoA
CH3-C-CH3
O
NAD+ + H+
CH3-C-CH2-COO-
O
2CH3C-SCoAO
CO2
Acetyl-CoA Acetoacetyl-CoA
Acetoacetate -Hydroxybutyrate
Acetone
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Protein CatabolismProtein Catabolism
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Nitrogen of Amino AcidsNitrogen of Amino Acids• -NH2 groups move freely by transaminationtransamination
• 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-COO-
NH2
CH
N
R-CH-COO-
E-Pyr PCH
O
E-Pyr P
CH2
N
R-C-COO-
E-Pyr P
+
CH2
NH2
E-Pyr P
R-C-COO-
O
An imine An isomericimine
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Nitrogen of Amino AcidsNitrogen of Amino Acids• nitrogens to be excreted are collected in glutamate,
which is oxidized to -ketoglutarate and NH4+
• NH4+ then enters the urea cycle
COO-
CH-NH3+
CH2
CH2
COO-
H2O
NAD+ NADHCOO-
C=O CH2
CH2
COO-
NH4+
Glutamate -Ketoglutarate
++
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The Urea Cycle - OverviewThe Urea Cycle - Overview• Urea cycle:Urea cycle: a cyclic pathway that produces urea
from CO2 and NH4+
+ NH4+CO2
2ATP
2ADP + 2H2O+
H3N-CHCH2COO-
COO-
H2N-C-OPO32-
O
H2N-C-NH2
O
C C
H
COO-H
-OOC
Carbamoyl phosphateAspartate
Ureacycle
UreaFumarate
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The Urea CycleThe Urea Cycle
H2N-C-OPO32-
O
(CH2)3
NH3+
CH-NH3+
COO-
(CH2)3
NH
CH-NH3+
COO-
C
NH2
O
(CH2)3
NH
CH-NH3+
COO-
C
NH2
N-CHCH2COO-COO-
H3N-CHCH2COO-COO-
+
Ornithine
Aspartate
Citrulline
Argininosuccinate
(next screen)
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The Urea CycleThe Urea Cycle
(CH2)3
NH3+
CH-NH3+
COO-
Ornithine
(CH2)3
NH
CH-NH3+
COO-
C
NH2
NH2+
Arginine
H2N-C-NH2
O
Urea
C CH
COO-H
-OOCFumarate
(CH2)3
NH
CH-NH3+
COO-
C
NH2
Argininosuccinate
N-CHCH2COO-
COO-
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Amino Acid CatabolismAmino Acid Catabolism• The breakdown of amino acid carbon skeletons
follows two pathways• glucogenic amino acidsglucogenic 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 acidsketogenic amino acids:: ones whose carbon skeletons are degraded to acetyl CoA or acetoacetyl CoA, both of which may then be converted to ketone bodies
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Amino Acid CatabolismAmino Acid CatabolismGlucogenicAspartateAsparagineAlanineGlycineSerineThreonineCysteineGlutamateGlutamineArginineProlineHistidineValineMethionine
KetogenicLeucineLysine
Glucogenic and KetogenicIsoleucinePhenylalanineTryptophanTyrosine
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Heme CatabolismHeme 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
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End End Chapter 27Chapter 27
Catabolic PathwaysCatabolic Pathways+ NH4
+CO2
2ATP
2ADP + 2H2O+
H3N-CHCH2COO-
COO-
H2N-C-OPO32-
O
H2N-C-NH2
O
C C
H
COO-H
-OOC
Carbamoyl phosphateAspartate
Ureacycle
UreaFumarate
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