122
PANEL 2–9: The Complete Citric Acid Cycle <TAGT>
+
NAD+
NADH + H
HS CoA
O
CH3 C
The complete citric acid cycle. The two
carbons from acetyl CoA that enter this
turn of the cycle (shadowed in red ) will
be converted to CO2 in subsequent turns
of the cycle: it is the two carbons
shadowed in blue that are converted to
CO2 in this cycle.
COO–
CO2
pyruvate
O
(2C)
acetyl CoA
CH3 C S CoA
+
COO–
COO–
COO–
CH2
HO C COO–
Step 1
oxaloacetate (4C)
Step 2
CH2
COO–
COO–
C O
CH2
COO–
Step 8
H C OH
CH2 malate (4C)
COO–
H2O
C O
CH2
COO–
NADH + H
NAD+
HS CoA
COO–
next cycle
CH2
citrate (6C)
HC COO–
oxaloacetate (4C)
HO CH
COO–
CITRIC ACID CYCLE
NAD+
Step 3
H2O
fumarate (4C)
Step 7
isocitrate (6C)
a-ketoglutarate (5C)
COO–
CH
succinyl CoA (4C)
succinate (4C)
CH
COO–
Step 6
COO–
CH2
H2O
Step 5
CH2
FADH2
Step 4
GTP
HS CoA
GDP
+
Pi
NADH + H
CH2
CH2
+
CO2
C O
COO–
CH2
CH2
NAD+
C O
COO–
FAD
COO–
COO–
HS CoA
S CoA
+
NADH + H
CO2
Details of the eight steps are shown below. For each step, the part of the molecule that undergoes a change is shadowed in blue,
and the name of the enzyme that catalyzes the reaction is in a yellow box.
STEP 1
After the enzyme
COO–
removes a proton from the
CH3 group on acetyl CoA,
C O
O C S CoA
the negatively charged
+
CH2– forms a bond to a
CH2
CH3
carbonyl carbon of
oxaloacetate. The
COO–
subsequent loss by
hydrolysis of the coenzyme
A (CoA) drives the reaction
strongly forward.
acetyl CoA
oxaloacetate
STEP 2
An isomerization
reaction, in which water is
first removed and then
added back, moves the
hydroxyl group from one
carbon atom to its neighbor.
O
citrate
synthase
COO–
C
H
HO
C
COO–
H
C
H
H
COO–
citrate
C
S CoA
COO–
H2O
CH2
CH2
HO
C
COO–
+ HS CoA + H+
COO–
CH2
COO–
COO–
COO–
H2O
H
H2O
C
CH2
S-citryl-CoA intermediate
aconitase
HO
citrate
COO–
H2O
C
H
H
C
H
C
COO–
H
C
COO–
C
H
HO
C
H
COO–
cis-aconitate intermediate
H2O
COO–
isocitrate
CHAPTER 2 PANELS
STEP 3
In the first of
four oxidation steps in the
cycle, the carbon carrying
the hydroxyl group is
converted to a carbonyl
group. The immediate
product is unstable, losing
CO2 while still bound to
the enzyme.
123
COO–
COO–
isocitrate
dehydrogenase
C
H
H
C
COO–
HO
C
H
H
H
H
NAD+ NADH + H+
COO–
isocitrate
COO–
C
H
H
C
H
C
COO–
H
C
H
C
O
C
O
+
CO2
H
COO–
COO–
oxalosuccinate intermediate
a-ketoglutarate
COO–
STEP 4
The a-ketoglutarate
dehydrogenase complex closely
resembles the large enzyme
complex that converts pyruvate
to acetyl CoA (pyruvate
dehydrogenase). It likewise
catalyzes an oxidation that
produces NADH, CO2, and a
high-energy thioester bond to
coenzyme A (CoA).
STEP 5
A phosphate
molecule from solution
displaces the CoA, forming a
high-energy phosphate
linkage to succinate. This
phosphate is then passed to
GDP to form GTP. (In bacteria
and plants, ATP is formed
instead.)
H
C
H
H
C
H
C
O
COO–
a-ketoglutarate dehydrogenase complex
+ HS CoA
NAD+
COO–
NADH + H
H
C
H
C
O
succinyl-CoA synthetase
S CoA
H
C
H
H
C
H
Pi
COO–
GDP
C
H
COO–
C
H
FAD
COO–
fumarate
COO–
fumarase
HO
C
H
H
C
H
COO–
HO
C
H
H
C
H
COO–
H2O
fumarate
COO–
H
C
FADH2
C
malate
H
succinate dehydrogenase
H
COO–
STEP 8
In the last of four
oxidation steps in the cycle, the
carbon carrying the hydroxyl
group is converted
to a carbonyl group,
regenerating the oxaloacetate
needed for step 1.
H
GTP
succinate
H
C
succinate
COO–
C
H
COO–
H2O
COO–
STEP 7
The addition of
water to fumarate places a
hydroxyl group next to a
carbonyl carbon.
C
H
C
O
COO–
succinyl-CoA
STEP 6
In the third
oxidation step in the cycle, FAD
removes two hydrogen atoms
from succinate.
H
succinyl-CoA
COO–
H
H
S CoA
a-ketoglutarate
C
C
+
CO2
H
H
malate
COO–
malate dehydrogenase
C
O
CH2
NAD
+
NADH + H
+
COO–
oxaloacetate
+ HS CoA