Appendix D
Two Important Metabolic Pathways
A-7
4
Two-carbon acetyl CoA is combined with
oxaloacetic acid, a 4-carbon compound. The
unstable bond between the acetyl group and
CoA is broken as oxaloacetic acid binds and
CoA is freed to prime another 2-carbon
fragment derived from pyruvic acid. The
product is the 6-carbon citric acid, for which
the cycle is named.
Bonds in the substrate are rearranged in
this step by the addition of a water molecule.
The product is malic acid.
The last oxidative step reduces another
NAD
+
and regenerates oxaloacetic acid, which
accepts a 2-carbon fragment from acetyl CoA
for another turn of the cycle.
A molecule of water is removed, and
another is added back. The net result is the
conversion of citric acid to its isomer, isocitric
acid.
The substrate loses a CO
2
molecule, and
the remaining 5-carbon compound is oxidized,
forming an
α
-ketoglutaric acid and reducing
NAD
+
.
This step is catalyzed by a multienzyme
complex very similar to the one that converts
pyruvic acid to acetyl CoA. CO
2
is lost; the
remaining 4-carbon compound is oxidized by
the transfer of electrons to NAD
+
to form
NADH+H
+
and is then attached to CoA by an
unstable bond. The product is succinyl CoA.
Substrate-level phosphorylation occurs in
this step. CoA is displaced by a phosphate group,
which is then transferred to GDP to form
guanosine triphosphate (GTP). GTP is similar to
ATP, which is formed when GTP donates a
phosphate group to ADP. The products of this
step are succinic acid and ATP.
In another oxidative step, two hydrogens are
removed from succinic acid (forming fumaric
acid) and transferred to FAD to form FADH
2
. The
function of this coenzyme is similar to that of
NADH+H
+
, but FADH
2
stores less energy. The
enzyme that catalyzes this oxidation-reduction
reaction is the only enzyme of the cycle that is
embedded in the mitochondrial membrane. All
other enzymes of the citric acid cycle are
dissolved in the mitochondrial matrix.
Pyruvic acid
from glycolysis
S
CoA
C O
Acetyl CoA (2C)
Citric acid (6C)
CH
3
COOH
Isocitric acid (6C)
CH
2
CH
2
H
2
O
H
2
O
HO C COOH
COOH
COOH
CoA
SH
FAD
Succinyl
CoA (4C)
CH
2
CH
2
C O
COOH
CH
2
P
i
CH
2
S CoA
GTP
GDP
ADP
C O
COOH
CH
2
CH
2
COOH
NAD
COOH
HO CH
CH
2
COOH
COOH
Fumaric
acid (4C)
Malic
acid
(4C)
CH
CH
COOH
Oxaloacetic
acid (4C)
COOH
C
O
CH
2
COOH
COOH
CH
2
CH
HO
HC COOH
α
-Ketoglutaric
acid (5C)
COOH
NAD
+
CO
2
Succinic
acid (4C)
NAD
+
CO
2
CoA
SH
CoA
SH
Krebs cycle
COOH
ATP
1
2
3
5
6
7
8
NADH+H
+
NADH+H
+
NADH+H
+
FADH
2
1
2
3
4
5
6
7
8
KREBS CYCLE (CITRIC ACID CYCLE)
All but one of the steps (step
6) occur in the mitochondrial matrix. The preparation of pyruvic
acid (by oxidation, decarboxylation, and reaction with coenzyme A)
to enter the cycle as acetyl CoA is shown above the cycle. Acetyl
CoA is picked up by oxaloacetic acid to form citric acid; and as it
passes through the cycle, it is oxidized four more times [forming
three molecules of reduced NAD (NADH
1
H
1
) and one of reduced
FAD (FADH
2
)] and decarboxylated twice (releasing 2 CO
2
). Energy is
captured in the bonds of GTP, which then acts in a coupled reaction
with ADP to generate one molecule of ATP by substrate-level
phosphorylation.
previous page 1149 Human Anatomy and Physiology (9th ed ) 2012 read online next page 1151 Human Anatomy and Physiology (9th ed ) 2012 read online Home Toggle text on/off