Chapter 28

Specific Catabolic Pathways:

Carbohydrate, Lipid, and
Protein Metabolism

1
 Convergence of Pathways

• Figure 28-2 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.

2
 Glycolysis
Glycolysis: A series of 10 enzyme-catalyzed reactions by which glucose is
oxidized to two molecules of pyruvate.
O
glycolysis
C6 H12 O 6 2CH3 CCOO- + 2H+
Glucose Pyruvate

• During glycolysis, there is net conversion of 2ADP to 2ATP.

O
C6 H12 O 6 + 2ADP + 2Pi 2CH3 CCOO- + 2ATP
Glucose Pyruvate

3
 Glycolysis
• Reaction 1: Phosphorylation of -D-glucose.

CH2 OH
HO O O O
HO hexokinase
+ -O-P-O-P-O-AMP
OH Mg2+
O- O-
a-D-Glucose OH ATP

CH2 OPO3 2-
HO O O
HO + -O-P-O-AMP
OH O-
OH
a-D-Glucose 6-phosphate ADP

4
 Glycolysis
• Reaction 2: Isomerization of -D-glucose 6-phosphate to -D-fructose 6-
phosphate.

6
6
CH2 OPO3 2- CH2 OPO3 2- 1
phosphohexose CH2OH
HO O O
isomerase
HO H HO 2
2 1 H OH
OH
OH HO H
a-D-Glucose 6-phosphate a-D-Fructose 6-phosphate

5
 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.

1
CHO H C OH 1 CH2 OH
H 2 OH C OH 2C O

HO H HO H HO H
H OH H OH H OH
H OH H OH H OH
CH2 OPO3 2- CH2 OPO3 2- CH2 OPO3 2-
Glucose 6-phosphate (An enediol) Fructose 6-phosphate

6
 Glycolysis
• Reaction 3: Phosphorylation of fructose 6-phosphate.
6
CH2 OPO3 2- 1
O CH2 OH phospho-
H HO fructokinase
+ ATP
H OH Mg2+
HO H
6
a-D-Fructose 6-phosphate CH2 OPO3 2- 1
O CH2 OPO3 2-
H HO + ADP
H OH
HO H
a-D-Fructose 1,6-bisphosphate

7
 Glycolysis
• Reaction 4: Cleavage of fructose 1,6-bisphosphate to two triose phosphates.

CH2 OPO 32- CH2OPO3 2-

C=O Dihydroxyacetone
C=O phosphate
HO H aldolase CH2OH
H OH CHO
H OH H C OH D-Glyceraldehyde
CH2 OPO 3 2- 2- 3-phosphate
CH2OPO3
Fructose 1,6-bisphosphate

8
 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 CHO
C=O H C OH
2- 2-
CH2 OPO 3 CH2 OPO3
Dihydroxyacetone D-Glyceraldehyde
phosphate 3-phosphate

9
 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.

glyceraldehyde
CHO 3-phosphate
H C OH + NAD+ + Pi dehydrogenase
CH2 OPO3 2- O
2-
D-Glyceraldehyde C-OPO3
3-phosphate H C OH + NADH
CH2 OPO3 2-
1,3-Bisphospho-
glycerate

10
 Glycolysis
Reaction 7: Transfer of a phosphate group from 1,3-bisphosphoglycerate to
ADP.
O phospho-
C-OPO3 2- O glycerate kinase
-
H C OH + O-P-O-AMP
CH2 OPO3 2- O- Mg 2+
1,3-Bisphospho-
ADP
glycerate -
COO O O
H C OH + -O-P-O-P-O-AMP
- -
CH2 OPO3 2- O O
3-Phosphoglycerate ATP

11
 Glycolysis
Reaction 8: Isomerization of 3-phosphoglycerate to
2-phosphoglycerate.

Reaction 9: Dehydration of 2-phosphoglycerate.

12
 Glycolysis
Reaction 10: Phosphate transfer to ADP and formation of ATP.

COO - pyruvate
O
kinase
C OPO3 2- + -O-P-O-AMP
- Mg2+
CH2 O
Phosphoenol- ADP
pyruvate
COO- O O
C=O + -O-P-O-P-O-AMP
- -
CH3 O O
Pyruvate ATP

13
 Glycolysis
Summing these 10 reactions gives the net equation for glycolysis:

glycolysis
C6 H12 O6 + 2NAD+ + 2HPO4 2- + 2ADP
Glucose
O
2CH3CCOO- + 2NADH + 2ATP + 2H2 O + 2H+
Pyruvate

14
 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.

aerobic conditions Acetyl CoA 13 Citric acid cycle

12 plants and animals
O OH
11 anaerobic conditions CH CHCOO-
CH3 CCOO - 3
contracting muscle
Pyruvate Lactate
10 anaerobic conditions
CH3CH2 OH + CO2
fermentation in yeast
Ethanol

15
 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 it.

16
 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.
O lactate
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 and M4 in skeletal muscle.

17
 Pyruvate to Lactate
• While reduction to lactate allows glycolysis to continue, it increases the
concentration of lactate and also of H+ in muscle tissue.
lactate OH
C6H12 O6 fermentation 2CH3 CHCOO - + 2H+
Glucose Lactate

• When blood lactate reaches about 0.4 mg/100 mL, muscle tissue becomes
almost completely exhausted.

18
 Pyruvate to Ethanol
Yeasts and several other organisms regenerate NAD+ by this two-step
pathway:
• Decarboxylation of pyruvate to acetaldehyde.
O pyruvate
O
- + decarboxylase
CH3 CCOO + H CH3 CH + CO 2
Pyruvate Acetaldehyde

• Acetaldehyde is then reduced to ethanol. NADH is the reducing agent.

Acetaldehyde is reduced and is the oxidizing agent in this redox reaction.
alcohol
O dehydrogenase
CH3 CH + NADH + H+
Acetaldehyde
CH3 CH2 OH + NAD+
Ethanol
19
 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.

O oxidative
CH3 CCOO - + NAD+ + CoASH decarboxylation
Pyruvate
O
CH3 CSCoA + CO2 + NADH
Acetyl-CoA

20
 Pentose Phosphate Pathway
• Figure 28-5
Simplified schematic
representation of the
pentose phosphate
pathway, also called
a shunt.

21
Energy Yield in Glycolysis-
Step Reaction(s) ATP produced
1, 2, 3 Activation (glucose -2
fructose 1,6-bisphosphate
5 Phosphorylation 4
2 (glyceraldehyde 3-phosphate
1,3-bisphosphoglycerate),
produces 2(NAD+ + H+ ) in cytosol
6, 9 Phosphate transfer to ADP 4
from 1,3-bisphosphoglycerate
and phosphoenolpyruvate
12 Oxidative decarboxylation 6
2 (pyruvate acetyl CoA),
produces 2(NAD+ + H+)
13 Oxidation to two acetyl CoA 24
in the citric acid cycle etc.
TOTAL 36
22
 Catabolism of Glycerol
• Glycerol enters glycolysis via dihydroxyacetone phosphate.

CH2 OH ATP ADP CH2 OH NAD+ NADH CH2 OH

CHOH CHOH C=O
CH2OH CH2 OPO3 2- CH2 OPO 32-
Glycerol Glycerol Dihydroxyacetone
1-phosphate phosphate

23
 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
(kcal•mol ) (kcal•g-1 )
-1

C6 H12 O6 + 6O 2 6CO 2 + 6H2O 686 3.8

Glucose
CH3(CH2)14 COOH + 23O2 16CO2 +16H2 O 2,340 9.3
Palmitic acid

24
 -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

25
 -Oxidation
• Reaction 2: Oxidation by FAD of the , carbon-carbon single bond to a
carbon-carbon double bond.

26
 -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.

27
 -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

28
 -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 eight cycles of
8CoA-SH b-oxidation
CH3(CH2)16 C-SCoA + 8NAD+
Octadecanoyl-CoA 8FAD
(Stearyl-CoA)
O
8NADH
9CH3 C-SCoA +
8FADH2
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.

29
 Energy Yield on -Oxidation
• Yield of ATP per mole of stearic acid (C18).
Step Chemical Step Happens ATP
1 Activation (stearic Once -2
acid -> stearyl CoA)
2 Oxidation (acyl CoA —> 8 times 16
trans-enoyl CoA)
produces FADH2
4 Oxidation (hydroxy- 8 times 24
acyl CoA to ketoacyl
CoA) produces NADH +H+
Oxidation of acetyl CoA 9 times 108
by the common metabolic
pathway, etc.
TOTAL 146

30
 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.

31
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 -COO-
Acetoacetate NAD+ + H+ b-Hydroxybutyrate

CO 2 O
CH3 -C-CH3
Acetone

32
Protein Catabolism
• Figure 28-7
Overview of
pathways in
protein
catabolism.

33
 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-COO- R-C-COO -

NH2 R-CH-COO - R-C-COO -

-H2 O +H2 O O
+ N N +
CH CH2
O NH2
E-Pyr P E-Pyr P
CH CH2
E-Pyr P An imine An isomeric
imine E-Pyr P
34
 Nitrogen of Amino Acids
Nitrogen atoms 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- +
COO-
CH-NH3
+ NAD NADH C=O
+
CH2 + H2 O CH2 + NH4
CH2 CH2
- -
COO COO
Glutamate a-Ketoglutarate

• NH4+ then enters the urea cycle.

35
 Urea Cycle—An Overview
Urea cycle: A cyclic pathway that produces urea from CO2 and NH4+.
CO2 + NH4 +
2ATP
2ADP + 2H2 O -
O + COO -
2- H3 N-CHCH2 COO
H2 N-C-OPO3 Aspartate
Carbamoyl phosphate

O Urea H COO-
H2 N-C-NH2 cycle C C
-
Urea OOC H
Fumarate

36
Urea Cycle COO
-

+
O H3 N-CHCH2 COO
-
NH2
H2 N-C-OPO 32- Aspartate
C O
NH3 + NH
(CH2 )3 (CH2 )3 NH2 COO-
CH-NH3 + CH-NH3
+
C N-CHCH2 COO -
-
COO COO- NH
Ornithine Citrulline (CH2)3
CH-NH3 +
COO-
Argininosuccinate

(nex t screen)
37
Urea Cycle
O
NH3 +
H2 N-C-NH2
Urea (CH2 )3
CH-NH3 +
COO -
NH2
Ornithine
C NH2 +
NH NH2 COO-
(CH2 )3 C N-CHCH2 COO-
NH
CH-NH3 +
(CH2 )3
COO - +
Arginine CH-NH3
H COO-
COO -
C C
-
OOC Argininosuccinate
H
Fumarate
38
 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.

39
Amino Acid
Figure 28-9
Catabolism
Catabolism
of the carbon
skeletons of
amino acids.

40
Amino Acid Catabolism

41
 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.

42
 Heme Catabolism
Figure 28-10 Heme degradation from heme to biliverdin to bilirubin.

43
 Heme Catabolism
Figure 28-11 A summary of catabolism showing the role of the common
metabolic pathway.

44
Chapter 28 Catabolic Pathways
CO2 + NH4 +
2ATP
2ADP + 2H2 O -
O + COO -
2- H3 N-CHCH2 COO
H2 N-C-OPO3 Aspartate
Carbamoyl phosphate

O Urea H COO-
H2 N-C-NH2 cycle C C
-
Urea OOC H
Fumarate
End
Chapter 28
45