Frederick A.

Bettelheim
William H. Brown
Mary K. Campbell
Shawn O. Farrell
www.cengage.com/chemistry/bettelheim

Chapter 28
Specific Catabolic Pathways:
Carbohydrate, Lipid, and Protein
Metabolism

William H. Brown • Beloit College

Convergence of Pathways
• Figure 28.2
Convergence
of the
specific
pathways of
carbohydrate
fat, and
protein
catabolism
into the
common
pathway.

28-2
Glycolysis
Glycolysis: A series of 10 enzyme-catalyzed reactions by
which glucose is oxidized to two molecules of pyruvate.
O
glycolysis
C 6 H1 2 O6 2 CH3 CCOO - + 2 H+
Glucose Pyruvate
• During glycolysis, there is net conversion of 2ADP to
2ATP.
O
C6 H1 2 O6 + 2 A DP + 2 P i 2 CH3 CCOO - + 2 A TP
Glucose Pyruvate

28-3
Glycolysis
• Reaction 1: Phosphorylation of -D-glucose.

CH2 OH
HO O O O
HO hexokinase
+ -O-P-O-P-O-AMP 2+
OH Mg
O- O-
-D-Glucose OH ATP

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

28-4
Glycolysis
• Reaction 2: Isomerization of glucose 6-phosphate to
fructose 6-phosphate.
6 6 2-
CH2 OPO3
2- CH2 OPO 3 1
phosphohexose CH2 OH
HO O isomerase O
HO H HO 2
2
OH
1 H OH
OH HO H
-D-Glucose 6-phosphate -D-Fructose 6-phosphate

28-5
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

28-6
Glycolysis
• Reaction 3: Phosphorylation of fructose 6-phosphate.
6
CH2 OPO 3 2 - 1
O CH2 OH phospho-
H HO fructokinase
+ A TP
H OH Mg 2 +
HO H
6
-D-Fructose 6-phosphate CH2 OPO 3 2 - 1
O CH2 OPO 3 2 -
H HO + A DP
H OH
HO H
-D-Fructose 1,6-bisphosphate

28-7
Glycolysis
• Reaction 4: Cleavage of fructose 1,6-bisphosphate to two
triose phosphates.
2- CH2 OPO3 2 -
CH2 OPO3
C= O Dihydroxyacetone
C=O phosphate
aldolase CH2 OH
HO H
H OH CHO
H OH D-Glyceraldehyde
H C OH
CH2 OPO3 2 - 2-
3-phosphate
CH2 OPO3
Fructose 1,6-bisphosphate

28-8
Glycolysis
• Reaction 5: Isomerization of triose phosphates.
• Catalyzed by phosphotriose isomerase.
• Only the D enantiomer of glyceraldehyde 3-phosphate
is formed.
CH2 OH CHO
C= O H C OH
2- 2-
CH2 OPO3 CH2 OPO3
Dihydroxyacetone D-Glyceraldehyde
phosphate 3-phosphate

28-9
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
+ dehydrogenase
H C OH + NAD + Pi
2-
CH2 OPO3 O
D-Glyceraldehyde C-OPO3 2 -
3-phosphate H C OH + NADH
2-
CH2 OPO3
1,3-Bisphospho-
glycerate

28-10
Glycolysis
Reaction 7: Transfer of a phosphate group from 1,3-
bisphosphoglycerate to ADP.
O phospho-
2-
C-OPO3 O glycerate kinase
-
H C OH + O-P-O-AMP
CH2 OPO3 2 - O- Mg2 +
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

28-11
Glycolysis
Reaction 8: Isomerization of 3-phosphoglycerate to 2-
phosphoglycerate.
COO- phosphoglycerate COO-
mutase 2-
H C OH H C OPO3
CH2 OPO3 2 - CH2 OH
3-Phosphoglycerate 2-Phosphoglycerate

Reaction 9: Dehydration of 2-phosphoglycerate.

- -
COO COO
enolase
H C OPO3 2 - 2+ C OPO 3
2-
+ H2 O
Mg
CH2 OH CH2
2-Phosphoglycerate Phosphoenolpyruvate

28-12
Glycolysis
Reaction 10:
10 Phosphate transfer to ADP.

COO- pyruvate
O kinase
2- -
C OPO3 + 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

28-13
Glycolysis
Summing these 10 reactions gives the net equation for
glycolysis:
glycolysis
C6 H1 2 O6 + 2 N A D+ + 2 HPO 4 2 - + 2 A DP
Glucose
O
2 CH3 CCOO - + 2 NADH + 2 ATP + 2 H 2 O + 2 H +
Pyruvate

28-14
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
CH3 CCOO CH3 CHCOO-
contracting muscle
Pyruvate Lactate
10 anaerobic conditions
CH3 CH2 OH + CO2
fermentation in yeast
Ethanol

28-15
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.

28-16
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 - + 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, M4 in skeletal muscle.

28-17
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
fermentation
C6 H1 2 O6 2 CH3 CHCOO- + 2 H+
Glucose Lactate

• When blood lactate reaches about 0.4 mg/100 mL,

muscle tissue becomes almost completely exhausted.

28-18
Pyruvate to Ethanol
Yeasts and several other organisms regenerate NAD+ by
this two-step pathway:
• Decarboxylation of pyruvate to acetaldehyde.
pyruvate
O O
- +
decarboxylase
CH3 CCOO + H CH3 CH + CO 2
Pyruvate Acetaldehyde
• Acetaldehyde is then reduced to ethanol. NADH is the
reducing agent. Acetaldehyde is oxidized and is the
reducing agent in this redox reaction.
alcohol
O dehydrogenase
+
CH3 CH + N AD H + H
Acetaldehyde CH3 CH2 OH + NA D +
Ethanol 28-19
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
decarboxylation
CH3 CCOO - + NA D+ + Co A S H
Pyruvate
O
CH3 CS Co A + CO2 + N A DH
Acetyl-CoA

28-20
Pentose Phosphate Pathway
• Figure 28.5 Simplified schematic representation of the
pentose phosphate pathway, also called a shunt.

28-21
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
28-22
Catabolism of Glycerol
• Glycerol enters glycolysis via dihydroxyacetone
phosphate.
CH2 OH ATP ADP CH2 OH NAD+ NADH CH2 OH
CHOH CHOH C=O
CH2 OH CH2 OPO3
2-
CH2 OPO3 2 -
Glycerol Glycerol Dihydroxyacetone
1-phosphate phosphate

28-23
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 H1 2 O6 + 6 O2 6 CO2 + 6 H2 O 686 3.8

Glucose
CH3 (CH2 ) 1 4 COOH + 2 3 O2 1 6 CO2 + 1 6 H2 O 2,340 9.3
Palmitic acid

28-24
-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-S CoA + AMP + 2 Pi
An acyl CoA

28-25
-Oxidation
• Reaction 2: Oxidation by FAD of the , carbon-carbon
single bond to a carbon-carbon double bond.
acyl-CoA
  O dehydrogenase
R-CH2 -CH2 -C-SCo A + FAD
An acyl-CoA O
H   C-S CoA
C C + FADH2
R H
A trans enoyl-CoA

28-26
-Oxidation
• Reaction 3: Hydration of the C=C double bond to give a
2° alcohol.
O OH
H C-S Co A enoyl-CoA O
+ H2 O hydratase C
C C R CH2 -C- S Co A
R H H
A trans enoyl-CoA An L--hydroxyacyl-CoA

• Reaction 4: Oxidation of the alcohol to a ketone.

OH
O -hydroxyacyl-CoA
C dehydrogenase
H CH2 -C-S Co A + NAD +
R
-Hydroxyacyl-CoA
O O
R-C-CH2 -C-SCoA + NADH + H+
-Ketoacyl-CoA 28-27
-Oxidation
• Reaction 5: Cleavage of the carbon chain by a molecule of
CoA-SH.
O O
thiolase
R-C-CH2 -C-S CoA + Co A-SH
-Ketoacyl-CoA Coenzyme A
O O
R-C-SCoA + CH3 C-SCoA
An acyl-CoA Acetyl-CoA

28-28
-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
8 CoA-S H -oxidation
CH3 ( CH2 ) 1 6 C-SCo A + 8 NAD
+

Octadecanoyl-CoA 8 FAD
(Stearyl-CoA)
O
9 CH3 C-SCoA + 8 NADH
8 FADH2
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.
28-29
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
28-30
Ketone Bodies
bodies Acetone, -hydroxybutyrate, and
• Ketone bodies:
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.

28-31
Ketone Bodies
HS -CoA
O O O
2 CH3 C-SCoA CH3 CCH2 C-SCo A
Acetyl-CoA Acetoacetyl-CoA

O NADH OH
CH3 -C-CH2 -COO- CH3 -CH-CH2 -COO-
NAD + H -Hydroxybutyrate
Acetoacetate + +

CO2 O
CH3 -C-CH3
Acetone

28-32
Protein Catabolism
• Figure 28.7
Overview of
pathways in
protein
catabolism.

28-33
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 -
R- CH-COO - R- C-COO -
N H2 O
- H2 O N + H2 O
+ N +
CH CH2
O N H2
E-Py r P E-Py r P
CH CH2
An imine An isomeric
E-Py r P E-Py r P
imine 28-34
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- +
COO-
CH-NH3 + NAD NADH C=O
CH2 + H2 O CH2 + NH4 +
CH2 CH2
COO- COO-
Glutamate -Ketoglutarate
• NH4+ then enters the urea cycle.

28-35
Urea Cycle—An Overview
Urea cycle: A cyclic pathway that produces urea from CO2
and NH4+.
CO2 + NH4 +
2 ATP

2 ADP + 2 H2 O -
+
COO
O
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 28-36
Urea Cycle
-
+
COO
O H3 N -CHCH2 COO -
N H2
H2 N -C- OPO 3 2 - Aspartate
C O
N H3 + NH
( CH2 ) 3 ( CH2 ) 3 N H2 COO-
CH- NH3 + CH- NH3 + C N -CHCH2 COO -
COO- COO- NH
Ornithine Citrulline ( CH2 ) 3
CH- NH3 +
COO-
Argininosuccinate

(next screen) 28-37

Urea Cycle
O
N H3 +
H2 N -C- NH2
( CH2 ) 3
Urea
CH- NH3 +
COO-
N H2
Ornithine
C N H2 +
NH N H2 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 28-38
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.

28-39
Amino Acid Catabolism
Figure 28.9
Catabolism
of the carbon
skeletons of
amino acids.

28-40
Amino Acid Catabolism

Glucogenic
Glucogenic Ketogenic and Ketogenic
Aspartate Leucine Isoleucine
Asparagine Lysine Phenylalanine
Alanine Tryptophan
Glycine Tyrosine
Serine
Threonine
Cysteine
Glutamate
Glutamine
Arginine
Proline
Histidine
Valine
Methionine

28-41
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.

28-42
Chapter 28 Catabolic Pathways
CO2 + NH4 +
2 ATP

2 ADP + 2 H2 O -
COO
O +
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
End Fumarate

Chapter 28 28-43