Transcript Chapter 20

Chapter 20
Specific Catabolic Pathways:
Carbohydrate, Lipid, and Protein
Metabolism
What is the General Outline of
Catabolic Pathway?

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
Carbohydrates are broken down by enzymes and
stomach acid to produce monosaccharides
Lipids are hydrolyzed by lipase to glycerol and fatty
acids or smaller units
Proteins are hydrolyzed by HCl and digestive enzyme in
the stomach and intestines to produce their constituent
amino acids
Convergence of Pathways
•
Figure 20.2
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.
Glycolysis
Glycolysis: A series of 10 enzyme-catalyzed reactions by
which glucose is oxidized to two molecules of pyruvate.
C6 H12 O 6
Glucose
glycolysis
O
2CH3 CCOO-
+
2H+
Pyruvate
• During glycolysis, there is net conversion of 2ADP to
2ATP.
C6 H12 O 6 + 2ADP
Glucose
+
2Pi
O
2CH3 CCOO- +
Pyruvate
2ATP
Glycolysis
•
Reaction 1: Phosphorylation of -D-glucose.
HO
HO
CH2 OH
O
O O
+ -O-P-O-P-O-AMP
OH
O- Oa-D-Glucose OH
ATP
HO
HO
CH2 OPO3 2O
hexokinase
Mg2+
O
+ -O-P-O-AMP
O-
OH
OH
a-D-Glucose 6-phosphate
ADP
Glycolysis
•
Reaction 2: Isomerization of -D-glucose 6-phosphate to
-D-fructose 6-phosphate.
6
CH2 OPO3 21
phosphohexose
CH2OH
O
HO
isomerase
H HO
2
HO
2
1
H
OH
OH
OH
HO
H
a-D-Glucose 6-phosphate
a-D-Fructose 6-phosphate
6
CH2 OPO3
O
2-
Glycolysis
This isomerization is most easily seen by considering the
open-chain forms of each monosaccharide. It is one ketoenol tautomerism followed by another.
1
CHO
H 2 OH
HO
H
H
OH
H
OH
CH2 OPO3 2Glucose 6-phosphate
H C OH
C OH
HO
H
H
OH
H
OH
CH2 OPO3 2(An enediol)
CH2 OH
2C O
HO
H
H
OH
H
OH
CH2 OPO3 2Fructose 6-phosphate
1
Glycolysis
•
Reaction 3: Phosphorylation of fructose 6-phosphate.
6
CH2 OPO3 21
CH2 OH
O
H HO
+ ATP
H
OH
HO
H
a-D-Fructose 6-phosphate
phosphofructokinase
Mg2+
6
CH2 OPO3 21
CH2 OPO3 2O
+ ADP
H HO
H
OH
HO
H
a-D-Fructose 1,6-bisphosphate
Glycolysis
•
Reaction 4: Cleavage of fructose 1,6-bisphosphate to two
triose phosphates.
2-
CH2OPO3 2Dihydroxyacetone
C=O
phosphate
CH2OH
CH2 OPO 3
C=O
aldolase
HO H
H OH
CHO
H OH
D-Glyceraldehyde
H C OH
3-phosphate
CH2 OPO 3 22CH2OPO3
Fructose 1,6-bisphosphate
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
C=O
2-
CH2 OPO 3
Dihydroxyacetone
phosphate
CHO
H C OH
2CH2 OPO3
D-Glyceraldehyde
3-phosphate
Glycolysis
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
CH2 OPO3 2D-Glyceraldehyde
3-phosphate
glyceraldehyde
3-phosphate
+ NAD+ + Pi dehydrogenase
O
2C-OPO3
H C OH
+ NADH
CH2 OPO3 21,3-Bisphosphoglycerate
Glycolysis
Reaction 7: Transfer of a phosphate group from 1,3bisphosphoglycerate to ADP.
O
C-OPO3 2+
H C OH
CH2 OPO3 21,3-Bisphosphoglycerate
O
O-P-O-AMP
O-
phosphoglycerate kinase
Mg 2+
ADP
O O
COO
+ -O-P-O-P-O-AMP
H C OH
2O
O
CH2 OPO3
3-Phosphoglycerate
ATP
Glycolysis
Reaction 8: Isomerization of 3-phosphoglycerate to
2-phosphoglycerate.
Reaction 9: Dehydration of 2-phosphoglycerate.
Glycolysis
Reaction 10: Phosphate transfer to ADP.
COO O
C OPO3 2- + -O-P-O-AMP
CH2
O
Phosphoenolpyruvate
pyruvate
kinase
Mg2+
ADP
O O
COOC=O + -O-P-O-P-O-AMP
CH3
O O
Pyruvate
ATP
Glycolysis
Summing these 10 reactions gives the net equation for
glycolysis:
C6 H12 O6 + 2NAD+ + 2HPO4 2- + 2ADP
Glucose
O
2CH3CCOOPyruvate
glycolysis
+ 2NADH + 2ATP + 2H2 O + 2H+
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.
12
aerobic conditions
plants and animals
Acetyl CoA 13
Citric acid cycle
OH
O
11 anaerobic conditions CH CHCOOCH3 CCOO 3
contracting muscle
Lactate
Pyruvate
10 anaerobic conditions
CH3CH2 OH + CO2
fermentation in yeast
Ethanol
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.
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.
lactate
O
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, M4 in skeletal muscle.
Pyruvate to Lactate
• While reduction to lactate allows glycolysis to continue,
it increases the concentration of lactate and also of H+
in muscle tissue.
C6H12 O6
Glucose
lactate
fermentation
OH
2CH3 CHCOO - + 2H+
Lactate
• When blood lactate reaches about 0.4 mg/100 mL,
muscle tissue becomes almost completely exhausted.
Pyruvate to Ethanol
Yeasts and several other organisms regenerate NAD+
by this two-step pathway:
• Decarboxylation of pyruvate to acetaldehyde.
O
-
+
CH3 CCOO + H
Pyruvate
pyruvate
decarboxylase
O
CH3 CH + CO 2
Acetaldehyde
• Acetaldehyde is then reduced to ethanol. NADH is
the reducing agent. Acetaldehyde is reduced and is
the oxidizing agent in this redox reaction.
O
CH3 CH + NADH + H+
Acetaldehyde
alcohol
dehydrogenase
CH3 CH2 OH + NAD+
Ethanol
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.
oxidative
O
CH3 CCOO - + NAD+ + CoASH decarboxylation
Pyruvate
O
CH3 CSCoA + CO2 + NADH
Acetyl-CoA
Pentose Phosphate Pathway
•
Figure 20.5
Simplified
schematic
representation of
the pentose
phosphate
pathway, also
called a shunt.
Energy Yield in Glycolysis
Step
1, 2, 3
Reaction(s)
Activation (glucose
fructose 1,6-bisphosphate
5
Phosphorylation
4
2 (glyceraldehyde 3-phosphate
1,3-bisphosphoglycerate),
produces 2(NAD+ + H+ ) in cytosol
4
Phosphate transfer to ADP
from 1,3-bisphosphoglycerate
and phosphoenolpyruvate
Oxidative decarboxylation
6
2 (pyruvate
acetyl CoA),
produces 2(NAD+ + H+)
Oxidation to two acetyl CoA
24
in the citric acid cycle etc.
TOTAL 36
6, 9
12
13
ATP produced
-2
Catabolism of Glycerol
•
Glycerol enters glycolysis via dihydroxyacetone phosphate.
CH2 OH
CHOH
CH2OH
Glycerol
ATP
ADP
CH2 OH
CHOH
+
NAD
CH2 OPO3 2Glycerol
1-phosphate
NADH
CH2 OH
C=O
CH2 OPO 32Dihydroxyacetone
phosphate
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
-1
(kcal•mol ) (kcal•g-1 )
C6 H12 O6 + 6O 2
Glucose
CH3(CH2)14 COOH + 23O2
Palmitic acid
6CO 2 + 6H2O
686
3.8
16CO2 +16H2 O
2,340
9.3
-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
-Oxidation
•
Reaction 2: Oxidation by FAD of the , carbon-carbon
single bond to a carbon-carbon double bond.
-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.
-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
-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
CH3(CH2)16 C-SCoA +
Octadecanoyl-CoA
(Stearyl-CoA)
8CoA-SH
8NAD+
8FAD
eight cycles of
b-oxidation
O
9CH3 C-SCoA +
Acetyl-CoA
8NADH
8FADH2
• -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.
Energy Yield on -Oxidation
•
Yield of ATP per mole of stearic acid (C18).
Step Chemical Step
Happens ATP
1
Activation (stearic
acid -> stearyl CoA)
Once
-2
2
Oxidation (acyl CoA —>
trans-enoyl CoA)
produces FADH2
8 times
16
4
Oxidation (hydroxyacyl CoA to ketoacyl
8 times
24
Oxidation of acetyl CoA 9 times
by the common metabolic
pathway, etc.
TOTAL
108
CoA) produces NADH +H+
146
Ketone Bodies
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•
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.
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 -COOAcetoacetate NAD+ + H+ b-Hydroxybutyrate
CO 2
O
CH3 -C-CH3
Acetone
Protein Catabolism
•
Figure 20.7
Overview of
pathways in
protein
catabolism.
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-COONH2
+
O
CH
E-Pyr P
R-CH-COO -H2 O
N
CH
E-Pyr P
An imine
R-C-COO
R-C-COO +H2 O O
N
+
CH2
NH2
E-Pyr P
CH2
An isomeric
E-Pyr P
imine
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+
+
NAD
CH-NH3
+ H2 O
CH2
CH2
COO
Glutamate
COONADH C=O
+
CH2
+ NH4
CH2
COO
a-Ketoglutarate
• NH4+ then enters the urea cycle.
Urea Cycle—An Overview
Urea cycle: A cyclic pathway that produces urea from CO2
and NH4+.
CO2 + NH4 +
2ATP
2ADP + 2H2 O
O
2H2 N-C-OPO3
Carbamoyl phosphate
O
H2 N-C-NH2
Urea
Urea
cycle
-
+ COO
H3 N-CHCH2 COO
Aspartate
COO-
H
-
C C
OOC
H
Fumarate
Urea Cycle
-
+
O
H2 N-C-OPO 32NH3 +
(CH2 )3
CH-NH3 +
COO
Ornithine
Citrulline
-
H3 N-CHCH2 COO
NH2
C O
NH
(CH2 )3
CH-NH3
COO-
COO
Aspartate
+
NH2 COOC N-CHCH2 COO NH
(CH2)3
CH-NH3 +
COOArgininosuccinate
(nex t screen)
Urea Cycle
O
NH3 +
(CH2 )3
CH-NH3 +
COO Ornithine
H2 N-C-NH2
Urea
NH2
C NH2 +
NH
(CH2 )3
CH-NH3 +
COO Arginine
-
NH2 COOC N-CHCH2 COONH
(CH2 )3
COO-
H
C C
OOC
H
Fumarate
+
CH-NH3
COO Argininosuccinate
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.
Amino Acid Catabolism
Figure 20.9
Catabolism of
the carbon
skeletons of
amino acids.
Amino Acid Catabolism
Hereditary Defects in Amino acid
Catabolism: PKU

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
Occurs in the absence of the enzyme phenylalanine
hydroxylase
If the enzyme is defective, phenylalanine is convert to
phenylpyruvate ( -ketoacid) instead of tyrosine
◦ Inhibits the conversion of pyruvate to acetyl CoA,
depriving the cells of energy via the common
catabolic pathway
◦ Results in mental retardation or PKU
(Phenylketonuria)
Prevention: restricting the intake of phenylalanine in
diet and artificial sweetener aspartate
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.
Heme Catabolism
Figure 20.10 Heme degradation from heme to biliverdin
to bilirubin.
The color change observed in bruises:
Black and blue are due to the congealed blood, green to the biliverdin
and yellow to the bilirubin
Heme Catabolism
Figure 20.11 A summary of catabolism showing the role
of the common metabolic pathway.