27 27-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e...

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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Chapter 27Chapter 27

Specific Catabolic Pathways:Specific Catabolic Pathways:

Carbohydrate, Lipid, Carbohydrate, Lipid,

and Protein Metabolismand Protein Metabolism

2727


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



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


+ + 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


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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

2727


-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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-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

2727


-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

2727


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

2727


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

2727


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

++

2727


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

2727


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)

2727


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

2727


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

27 27-1 © 2003 Thomson Learning, Inc. All rights reserved General, Organic, and Biochemistry, 7e...

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