Organic Chemistry

1050 CHAPTER 25 The Organic Mechanisms of the Coenzymes • Metabolism

capable of entering the citric acid cycle (Figure 25.3). The final product of carbohydrate

metabolism is pyruvate (Figure 25.2). To enter the carboxylic acid cycle, pyruvate must

be converted either to acetyl-CoA or to oxaloacetate (Section 25.5)—a citric acid cycle

intermediate.

The pyruvate dehydrogenase systemis a group of three enzymes responsible for the

conversion of pyruvate to acetyl-CoA. The pyruvate dehydrogenase system requires

TPP and four other coenzymes: lipoate, coenzyme A, FAD, and

The first enzyme in the system catalyzes the reaction of TPP with pyruvate to

form the same resonance-stabilized carbanion formed by pyruvate decarboxylase

and by the enzyme in Problems 8 and 9. The second enzyme of the system ( ) re-

quires lipoate, a coenzyme that becomes attached to its enzyme by forming an

amide with the amino group of a lysine side chain. The disulfide linkage of lipoate is

cleaved when it undergoes nucleophilic attack by the carbanion. In the next step, the

TPP carbanion is eliminated from the tetrahedral intermediate. Coenzyme A

(CoASH)reacts with the thioester in a transthioesterification reaction (one thioester

is converted into another), substituting coenzyme A for dihydrolipoate. At this point,

the final reaction product (acetyl-CoA) has been formed. However, before another

catalytic cycle can occur, dihydrolipoate must be oxidized back to lipoate. This is

done by the third enzyme an FAD-requiring enzyme (Section 25.3). Oxidation

of dihydrolipoate by FAD forms enzyme-bound then oxidizes

back to FAD.

The vitamin precursor of CoASH is pantothenate. We have seen that CoASH is

used in biological systems to activate carboxylic acids by converting them into

thioesters, which are much more reactive toward nucleophilic acyl substitution reac-

FADH 2

FADH 2 .NAD+

(E 3 ),

E 2

pyruvate

+ CoASH + CO 2

O O

CH 3 C C O−

acetyl-CoA

O

CH 3 C SCoA

pyruvate dehydrogenase

system

NAD+.

3-D Molecule:

Coenzyme A

CoASH

S S NAD+NADH + H+

O

C

NH(CH 2 ) 4 E 2 FADH 2 E 3

CH 3

+

+

SCoA+ C

N S

+

R

SH SH

O

C

NH(CH 2 ) 4 E 2

C

O

FAD E 3

FAD E 3

CH 3 S SH

O

C

NH(CH 2 ) 4 E 2

C

O

−

acetyl-CoA dihydrolipoate

−B

H B

C

resonance-stabilized

carbanion

mechanism for the pyruvate dehydrogenase system

N S

+ S S

O

C

R NH(CH 2 ) 4 E 2

CH 3 C−

OH

+ NCS

SH

+

O

R C

NH(CH 2 ) 4 E 2

C

OH

CH 3 S

lipoate