Download Camp 1 - Dr. Paul J. McElligott

27
General, Organic, and
Biochemistry, 7e
Bettelheim,
Brown, and March
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27-1
27Chapter 27
Specific Catabolic Pathways:
Carbohydrate, Lipid,
and Protein Metabolism
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27-2
27Glycolysis
• Glycolysis: a series of 10 enzyme-catalyzed
reactions by which glucose is oxidized to two
molecules of pyruvate
C6 H1 2 O6
Glucos e
glycolys is
O
2 CH3 CCOO - + 2 H+
Pyruvate
• there is net conversion of 2ADP to 2ATP
C6 H1 2 O6 + 2 ADP + 2 Pi
Glucose
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O
2 CH3 CCOO - + 2 ATP
Pyruvate
27-3
27Glycolysis - Rexn 1
• reaction 1: phosphorylation of -D-glucose
HO
HO
CH2 OH
O
O O
+ -O-P-O-P-O-AMP
OH
-D -Glucose OH
HO
HO
-
O
-
O
ATP
CH 2 OPO3
O
2-
OH
OH
-D -Glucose 6-p hosphate
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hexokinas e
2+
Mg
O
+ - O-P-O-AMP
O
ADP
27-4
27Glycolysis - Rexn 2
• reaction 2: isomerization of glucose 6-phosphate
to fructose 6-phosphate
6
HO
HO
6
2-
CH2 OPO3
O
2
OH
ph os phoglu coisomeras e
1
OH
-D-Glu cose 6-phosp hate
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2-
CH2 OPO3
1
CH2 OH
O
H HO
2
H
OH
HO
H
-D -Fru ctos e 6-phosp hate
27-5
27Glycolysis - 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
1
CHO
H 2 OH
HO
H
H
OH
H
OH
CH2 OPO3 2 Glucose 6-p hos phate
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H C OH
C OH
HO
H
H
OH
H
OH
CH2 OPO3 2(A n ened iol)
1
CH2 OH
2C O
HO
H
H
OH
H
OH
CH2 OPO3 2 Fru ctose 6-phosp hate
27-6
27Glycolysis - Rexn 3
• reaction 3: phosphorylation of fructose 6-
phosphate
6
CH2 OPO3 2 1
CH2 OH
O
H HO
+ ATP
H
OH
HO
H
-D -Fru ctose 6-phosp hate
phosph ofructokin ase
Mg 2+
6
2-
CH2 OPO3
1
CH2 OPO3 2 O
+ ADP
H HO
H
OH
HO
H
-D-Fructose 1,6-bis phosp hate
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27-7
27Glycolysis - Rexn 4
• reaction 4: cleavage of fructose 1,6-bisphosphate
to two triose phosphates
CH2 OPO3
2-
C=O
HO
H
H
al dol ase
H
OH
OH
CH2 OPO3 2 -
Fructose 1,6-b isph osp hate
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CH2 OPO3 2 C=O
CH2 OH
CHO
H C OH
CH2 OPO3 2 -
D ih yd roxyacetone
p hos phate
D -Glyceraldehyde
3-p hosph ate
27-8
27Glycolysis - Rexn 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
CH2 OH
C= O
CHOH
C-OH
CH2 OPO 3 2 -
CH2 OPO 3 2 -
Dihydroxyacetone
phosphate
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An enediol
intermediate
CHO
H C OH
CH2 OPO 3 2 D-Glyceraldehyde
3-phosphate
27-9
27Glycolysis - Rexn 6
• 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
2CH2 OPO3
D -Glyceraldehyde
3-ph os phate
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+
+ NAD + Pi
glyceraldeh yd e
3-p hosphate
d ehydrogenase
O
2C-OPO3
H C OH
+ NADH
2CH2 OPO3
1,3-Bis phosp hoglycerate
27-10
27Glycolysis - Rexn 7
• Reaction 7: transfer of a phosphate group from
1,3-bisphosphoglycerate to ADP
O
2C-OPO3
+
H C OH
CH2 OPO3 2 1,3-Bisp hos phoglycerate
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O
O-P-O-AMP
O-
phosp hoglycerate kinas e
Mg 2 +
AD P
COOO O
+ -O-P-O-P-O-AMP
H C OH
O O
CH2 OPO3 2 3-Ph os phoglycerate
ATP
27-11
27Glycolysis - Rexn 8 & 9
• Reaction 8: isomerization of 3-phosphoglycerate
to 2-phosphoglycerate
phosph oglycerate
COOCOOmutas e
H C OH
H C OPO3 2 CH2 OH
CH2 OPO3 22-Ph os phoglycerate
3-Phos phoglycerate
• Reaction 9: dehydration of 2-phosphoglycerate
COOCOOen olase
22+ H2 O
H C OPO3
C
OPO
2+
3
Mg
CH2 OH
CH2
2-Phosph oglycerate
Phosph oen olp yruvate
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27-12
27Glycolysis - Rexn 10
• Reaction 10: phosphate transfer to ADP
-
COO
O
2C OPO3
+ O-P-O-AMP
CH2
OPh os phoenolpyruvate
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pyru vate
kinas e
Mg2 +
AD P
O O
COOC=O + O-P-O-P-O-AMP
O- OCH3
A TP
Pyruvate
27-13
27Glycolysis
• Summing these 10 reactions gives the net
equation for glycolysis
C6 H1 2 O6 + 2 N A D+ + 2 HPO 4 2 - + 2 A DP
Glucos e
O
2 CH3 CCOO - + 2 NADH +
Pyruvate
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glycolys is
2 ATP + 2 H 2 O + 2 H +
27-14
27Reactions 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
p lants and animals
Acetyl CoA
13
Citric acid cycle
OH
O
- 11 anaerob ic conditions
CH3 CHCOOCH3 CCOO
contracting mu scle
Lactate
Pyruvate
10 anaerob ic conditions
CH3 CH2 OH + CO2
fermentation in yeast
Ethanol
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27-15
27Reactions 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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27-16
27Pyruvate to Lactate
• in vertebrates under anaerobic conditions, the most
important pathway for the regeneration of NAD+ is
reduction of pyruvate to lactate
lactate
O
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, and M4 in skeletal muscle
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27-17
27Pyruvate to Lactate
• while reduction to lactate allows glycolysis to continue,
it increases the concentration of lactate and also of H+
in muscle tissue
C6 H1 2 O6
Glucos e
lactate
fermentation
OH
2 CH3 CHCOO- + 2 H+
Lactate
• when blood lactate reaches about 0.4 mg/100 mL,
muscle tissue becomes almost completely exhausted
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27-18
27Pyruvate to Ethanol
• Yeasts and several other organisms regenerate
NAD+ by this two-step pathway
• decarboxylation of pyruvate to acetaldehyde
pyruvate
O
decarboxylase
+
CH3 CCOO + H
Pyruvate
O
CH3 CH + CO 2
Acetaldehyde
• reduction of acetaldehyde to ethanol
alcohol
O
dehydrogenase
+
CH3 CH + N AD H + H
Acetaldehyde
CH3 CH2 OH + NA D +
Ethanol
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27-19
27Pyruvate 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
oxidative
O
decarboxylation
CH3 CCOO - + NAD+ + CoASH
Pyruvate
O
CH3 CSCoA + CO2 + N ADH
Acetyl-CoA
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27-20
27Energy Yield of Glycolysis
Step
1, 3
5
6, 9
12
13
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Reaction(s)
Activation (glucose ->
fru ctose 1,6-bisp hosphate
ATP prod uced
-2
4
Oxidative phosp horylation
(2 glyceraldeh yd e 3-phosph ate ->
1,3-bis phosph oglycerate),
produces 2N AD +
4
Ph os phate transfer to A DP
from 1,3-bisph os phoglycerate
and phosph oen olp yruvate
6
Oxidative decarboxylation
(2 pyruvate -> acetyl CoA),
produces 2N AD +
24
Oxidation to tw o acetyl CoA
in th e citric acid cycle etc.
TOTAL 36
27-21
27Catabolism of Glycerol
• Glycerol enters glycolysis via dihydroxyacetone
phosphate
CH2 OH ATP
CHOH
CH2 OH
Glycerol
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ADP
+
NAD
CH2 OH
CHOH
CH2 OPO3 2Glycerol
1-phosph ate
NADH
CH2 OH
C=O
CH2 OPO3 2 D ihydroxyacetone
phosp hate
27-22
27Fatty 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
(k cal• mol ) (kcal• g -1)
C6 H1 2 O6 + 6 O2
Glucose
CH3 (CH2 ) 1 4 COOH + 2 3 O2
Palmitic acid
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6 CO2 + 6 H2 O
686
3.8
1 6 CO2 +1 6 H2 O 2,340
9.3
27-23
27b-Oxidation
• b-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 + 2 Pi
An acyl CoA
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27-24
27b-Oxidation
• Reaction 2: oxidation of the ,b carbon-carbon single
bond to a carbon-carbon double bond
acyl-CoA
O
b

dehydrogenase
R- CH2 -CH2 - C-SCo A + FAD
O
An acyl-CoA
H
C-SCo A
+ FAD H2
C C
R
H
A trans enoyl-CoA
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27-25
27b-Oxidation
• Reaction 3: hydration of the double bond
O
enoyl-CoA
H
C-SCo A
hydratas e
+
C C
H2 O
R
H
A trans enoyl-CoA
OH
R
C
H
O
CH2 -C- SCoA
An L- b-hydroxyacyl-CoA
• Reaction 4: oxidation of the 2alcohol to a ketone
OH
C
H
O
CH2 -C-SCoA
R
b-Hyd roxyacyl-CoA
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+ NAD+
b-h yd roxyacyl-CoA
dehydrogenas e
O
O
R-C-CH2 -C-SCoA + NADH + H+
b-Ketoacyl-CoA
27-26
27b-Oxidation
• Reaction 5: cleavage of the carbon chain by a molecule
of CoA-SH
O
O
th iolas e
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
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27-27
27b-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
O
CH3 ( CH2 ) 1 6 C-SCoA +
Octadecanoyl-CoA
(Stearyl-CoA)
8 CoA-SH
+
8 NAD
8 FAD
eigh t cycles of
b-oxidation
O
9 CH3 C-SCoA +
A cetyl-CoA
8 NADH
8 FADH2
• b-oxidation of unsaturated fatty acids proceeds in the
same way, with an extra step that isomerizes the cis
double
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27-28
27Energy Yield from b-Oxidation
• Yield of ATP per mole of stearic acid (C18)
Step Chemical Step
Happ ens ATP
1
Activation (stearic
acid -> stearyl CoA)
Once
-2
2
Oxidation (acyl CoA ->
trans-enoyl CoA)
produces FA D H 2
8 times
16
4
Oxidation (hydroxyacyl CoA to ketoacyl
CoA ) produ ces N A D H
8 times
24
Oxidation of acetyl CoA
9 times
by the common metabolic
path w ay, etc.
TOTAL
108
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146
27-29
27Ketone Bodies
• Ketone bodies: acetone, b-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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27-30
27Ketone Bodies
O
2 CH3 C-SCoA
Acetyl-CoA
HS-CoA
O
O
CH3 CCH2 C-SCoA
Acetoacetyl-CoA
O
NADH
OH
CH3 -C-CH2 -COOCH3 -CH-CH2 -COOA cetoacetate
NAD+ + H+ b-Hyd roxybutyrate
CO2
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O
CH3 -C-CH3
Acetone
27-31
27
Protein Catabolism
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27-32
27Nitrogen of Amino Acids
• -NH2 groups move freely by transamination
• 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-COONH2
+
O
CH
E-Pyr P
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R-CH-COO-
R-C-COO-
N
CH
N
CH2
E-Pyr P
E-Pyr P
An imine
A n isomeric
imine
R-C-COOO
+
NH2
CH2
E-Pyr P
27-33
27Nitrogen of Amino Acids
• nitrogens to be excreted are collected in glutamate,
which is oxidized to -ketoglutarate and NH4+
-
COO
+
+
NAD
CH-NH3
+ H2 O
CH2
CH2
COOGlu tamate
-
COO
NADH C=O
CH2
+ NH4 +
CH2
COO-Ketoglutarate
• NH4+ then enters the urea cycle
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27-34
27The Urea Cycle - Overview
• Urea cycle: a cyclic pathway that produces urea
from CO2 and NH4+
+
CO2 + NH4
2 ATP
2 ADP + 2 H2 O
+
O
2-
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-
H3 N-CHCH2 COO
Aspartate
H2 N-C-OPO3
Carbamoyl p hosphate
O
H 2 N-C-NH2
Urea
COO-
COO-
H
Urea
cycle
C C
-
OOC
H
Fumarate
27-35
27The Urea Cycle
-
O
H 2 N-C-OPO3
NH3
+
( CH2 ) 3
CH-NH3 +
-
COO
Orn ithine
2-
+ COO
H 3 N-CHCH2 COOAs partate
NH2
C O
NH
( CH2 ) 3
CH-NH3
+
COOCitru llin e
NH2 COOC N-CHCH2 COO
NH
( CH 2 ) 3
CH-NH3 +
COOA rgininosu ccinate
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(next s creen )
27-36
27The Urea Cycle
O
H2 N -C- NH2
Urea
N H3 +
( CH2 ) 3
CH- NH3 +
COOOrnithine
N H2
C N H2 +
NH
N H2 COOC N -CHCH2 COO NH
( CH2 ) 3
CH- NH3 +
COOArginine
COO-
H
-
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( CH2 ) 3
C C
OOC
H
Fumarate
CH- NH3 +
COOArgininosuccinate
27-37
27Amino Acid Catabolism
• The breakdown of amino acid carbon skeletons
follows two pathways
• glucogenic 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 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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27-38
27Amino Acid Catabolism
Glucogenic
Aspartate
Asparagine
Alanine
Glycine
Serine
Threonine
Cysteine
Glutamate
Glutamine
Arginine
Proline
Histidine
Valine
Methionine
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Ketogenic
Leucine
Lys ine
Glucogenic
and Ketogenic
Is oleucine
Phenylalanine
Tryptophan
Tyrosine
27-39
27Heme 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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27-40
27Catabolic Pathways
+
CO2 + NH4
2 ATP
2 ADP + 2 H2 O
+
O
2-
End
Chapter 27
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-
H3 N-CHCH2 COO
Aspartate
H2 N-C-OPO3
Carbamoyl p hosphate
O
H 2 N-C-NH2
Urea
COO-
COO-
H
Urea
cycle
C C
-
OOC
H
Fumarate
27-41