Download Oxidation

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.
C6 H1 2 O6
Glucos e
glycolys is
O
2 CH3 CCOO - + 2 H+
Pyruvate
• During glycolysis, there is net conversion of 2ADP to
2ATP.
C6 H1 2 O6 + 2 ADP + 2 Pi
Glucose
O
2 CH3 CCOO - + 2 ATP
Pyruvate
28-3
Glycolysis
• 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
hexokinas e
2+
Mg
2-
OH
OH
-D -Glucose 6-p hosphate
O
+ - O-P-O-AMP
O
ADP
28-4
Glycolysis
• Reaction 2: Isomerization of glucose 6-phosphate to
fructose 6-phosphate.
6
2-
6
2-
CH2 OPO3
CH2 OPO3
1
ph os phohexose
CH2 OH
O
O
HO
isomeras e
H HO
2
HO
2
1
H
OH
OH
OH
HO
H
-D-Glu cose 6-phosp hate
-D -Fru ctos e 6-phosp hate
28-5
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 2 Glucose 6-p hos phate
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
28-6
Glycolysis
• Reaction 3: Phosphorylation of fructose 6-phosphate.
6
CH2 OPO 3 2 - 1
CH2 OH
O
H HO
+ A TP
H
OH
HO
H
-D-Fructose 6-phosphate
phosphofructokinase
Mg 2 +
6
CH2 OPO 3 2 - 1
CH2 OPO 3 2 O
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.
CH2 OPO3
2-
C=O
HO
H
H
al dol ase
H
OH
OH
CH2 OPO3 2 -
Fructose 1,6-b isph osp hate
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
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
H C OH
C=O
CH2 OPO3
2-
D ih yd roxyaceton e
ph os phate
CH2 OPO3
2-
D-Glyceraldehyde
3-p hosph ate
28-9
Glycolysis
Reaction 6: Oxidation of the -CHO group of Dglyceraldehyde 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
+
+ NAD + Pi
glyceraldeh yd e
3-p hosphate
d ehydrogenase
O
2C-OPO3
H C OH
+ NADH
2CH2 OPO3
1,3-Bis phosp hoglycerate
28-10
Glycolysis
Reaction 7: Transfer of a phosphate group from 1,3bisphosphoglycerate to ADP.
O
2C-OPO3
+
H C OH
CH2 OPO3 2 1,3-Bisp hos phoglycerate
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
28-11
Glycolysis
Reaction 8: Isomerization of 3-phosphoglycerate to 2phosphoglycerate.
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
28-12
Glycolysis
Reaction 10: Phosphate transfer to ADP.
-
COO
O
2C OPO3
+ O-P-O-AMP
CH2
OPh os phoenolpyruvate
pyru vate
kinas e
Mg2 +
AD P
O O
COOC=O + O-P-O-P-O-AMP
O- OCH3
A TP
Pyruvate
28-13
Glycolysis
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
glycolys is
2 ATP + 2 H 2 O + 2 H +
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.
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
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.
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, 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.
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.
28-18
Pyruvate 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
• 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.
oxidative
O
decarboxylation
CH3 CCOO - + NAD+ + CoASH
Pyruvate
O
CH3 CSCoA + CO2 + N ADH
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
1, 2, 3
Reaction(s)
Activation (glucose
fru ctose 1,6-bisp hosphate
ATP prod uced
5
Ph os phorylation
2 (glyceraldeh yd e 3-phosph ate
1,3-bis phosph oglycerate),
produces 2(N AD + + H+ ) in cytosol
4
6, 9
Ph os phate transfer to A DP
from 1,3-bisph os phoglycerate
and phosph oen olp yruvate
4
12
Oxidative decarboxylation
2 (pyruvate
acetyl CoA),
produces 2(N AD + + H + )
6
13
Oxidation to tw o acetyl CoA
in th e citric acid cycle etc.
TOTAL
-2
24
36
28-22
Catabolism of Glycerol
• Glycerol enters glycolysis via dihydroxyacetone
phosphate.
CH2 OH ATP
CHOH
CH2 OH
Glycerol
ADP
+
NAD
CH2 OH
CHOH
CH2 OPO3 2Glycerol
1-phosph ate
NADH
CH2 OH
C=O
CH2 OPO3 2 D ihydroxyacetone
phosp hate
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
-1
(k cal• mol ) (kcal• g -1)
C6 H1 2 O6 + 6 O2
Glucose
CH3 (CH2 ) 1 4 COOH + 2 3 O2
Palmitic acid
6 CO2 + 6 H2 O
686
3.8
1 6 CO2 +1 6 H2 O 2,340
9.3
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-SCoA + 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.

 O
R-CH2 -CH2 -C-SCoA
A n acyl-CoA
+ FAD
acyl-CoA
dehydrogen ase
O
H   C-SCoA
+ FADH2
C C
R
H
A trans enoyl-CoA
28-26
-Oxidation
• Reaction 3: Hydration of the C=C double bond to give a
2° alcohol.
O
enoyl-CoA
H
C-SCo A
hydratas e
+ H2 O
C C
R
H
A trans enoyl-CoA
OH
R
C
H
O
CH2 -C- SCoA
An L- -hydroxyacyl-CoA
• Reaction 4: Oxidation of the 2 alcohol to a ketone.
OH
C
H
O
CH2 -C-SCoA
R
-Hyd roxyacyl-CoA
+ NAD+
-h yd roxyacyl-CoA
dehydrogenas e
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
th iolas e
+
R-C-CH2 -C-SCoA
CoA-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
CH3 ( CH2 ) 1 6 C-SCoA +
Octadecanoyl-CoA
(Stearyl-CoA)
8 CoA-SH
+
8 NAD
8 FAD
eigh t cycles of
-oxidation
O
9 CH3 C-SCoA +
A cetyl-CoA
8 NADH
8 FADH2
• -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
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 (hydroxy8 times
acyl CoA to ketoacyl
CoA ) produ ces N A D H +H +
24
Oxidation of acetyl CoA
9 times
by the common metabolic
path w ay, etc.
TOTAL
108
146
28-30
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.
28-31
Ketone 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+ -Hyd roxybutyrate
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 RCH-COO
N H2
- H2 O N
+
CH
O
E-Py r P
CH
An imine
E-Py r P
RC-COO
R- C-COO + H2 O O
N
+
CH2
N H2
E-Py r P
CH2
An is omeric
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
+
+
NAD
CH-NH3
+ H2 O
CH2
CH2
COOGlu tamate
-
COO
NADH C=O
CH2
+ NH4 +
CH2
COO-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
+
O
-
H3 N-CHCH2 COO
Aspartate
2-
H2 N-C-OPO3
Carbamoyl p hosphate
O
H 2 N-C-NH2
Urea
COO-
COO-
H
Urea
cycle
C C
-
OOC
H
Fumarate
28-36
Urea Cycle
O
N H3 +
N H2
C O
NH
( CH2 ) 3
( CH 2 ) 3
H2 N -C- OPO 3 2 -
CH- NH3 +
COOOrnithine
CH- NH3 +
COOCitrulline
COO
+
H3 N -CHCH2 COO As partate
N H2 COOC N -CHCH 2 COO NH
( CH2 ) 3
CH- NH3 +
COOArgininosuccinate
(next screen)
28-37
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
( CH2 ) 3
COO-
H
-
C C
OOC
H
Fumarate
CH- NH3 +
COOArgininosuccinate
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
Aspartate
Asparagine
Alanine
Glycine
Serine
Threonine
Cysteine
Glutamate
Glutamine
Arginine
Proline
Histidine
Valine
Methionine
Ketogenic
Leucine
Lys ine
Glucogenic
and Ketogenic
Is oleucine
Phenylalanine
Tryptophan
Tyrosine
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
+
O
2-
End
Chapter 28
-
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
28-43