Panel 132 The complete citric acid cycle

NAD+ NADH + H
+

O CH3 C COO CO2 O

HS CoA

pyruvate

acetyl CoA (2C)

CH3 C S CoA COO C O CH2 COO

oxaloacetate (4C)

HS CoA H2O COO CH2 HO C COO CH2 COO

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.

next cycle
+

NADH + H NAD+

COO
Step 8

Step 1

Step 2

COO

H C OH CH2 malate (4C) COO H2O

C O CH2 COO
oxaloacetate (4C)

COO HC COO HO CH COO CH2

isocitrate (6C)

citrate (6C)

CITRIC ACID CYCLE Step 3

NAD+

fumarate (4C) Step 7

COO
-ketoglutarate (5C) succinyl CoA (4C)

NADH + H

COO CH CH COO
FADH2
succinate (4C) Step 6

CH2 CH2 C O COO

CO2

COO CH2 CH2

Step 5

H2O

COO CH2 CH2 C O

Step 4

NAD+

FAD

COO
GTP GDP + Pi

S CoA CO2

HS CoA
NADH + H
+

HS CoA

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 removes a proton from the CH3 group on acetyl CoA, the negatively O C S CoA charged CH2 forms a bond to a carbonyl carbon CH3 of oxaloacetate. The subsequent loss by hydrolysis of the coenzyme A (CoA) drives the reaction strongly acetyl CoA forward.

COO + C CH2 COO O

O
citrate synthase

C CH2

S CoA

H2O

COO CH2 + HS CoA + H+

HO

C CH2

COO

HO

C CH2

COO

COO
oxaloacetate S-citryl-CoA intermediate

COO
citrate

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.

COO H HO H C C C H COO H
aconitase

H2O H

COO C C C H COO H

H2O H H H2O HO

COO C C C H COO H

COO
citrate

H2O

COO
cis-aconitate intermediate

COO
isocitrate

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.

COO H H HO C C C H COO H
NAD+ NADH + H
+

COO
isocitrate dehydrogenase

COO H H
H
+

H H

C C C

H COO O
CO2

C C C

H H O

COO
isocitrate

COO
oxalosuccinate intermediate

COO
a-ketoglutarate

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).

COO H H C C C H H O
NAD+ NADH + H
+

COO
a-ketoglutarate dehydrogenase complex + HS CoA

H H

C C C

H H O

COO
a-ketoglutarate

S CoA
CO2 succinyl-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.)

COO H H C C C H H O H2O
Pi succinyl-CoA synthetase

COO H H
GDP GTP
succinate

C C

H H
+ HS CoA

COO

S CoA
succinyl-CoA

Step 6

In the third oxidation step in the cycle, FAD removes two hydrogen atoms from succinate.

COO H H C C H H

COO
succinate dehydrogenase

C H
FAD FADH2

C COO

COO
succinate

fumarate

Step 7

The addition of water to fumarate places a hydroxyl group next to a carbonyl carbon.

COO C H C COO
fumarate

fumarase

COO HO H C C H H

H2O

COO
malate

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.

COO HO H C C H H

malate dehydrogenase

COO C CH2 O

COO
malate

NAD

NADH + H

COO
oxaloacetate