Organic Chemistry

Section 17.20 Synthesis of Carboxylic Acid Derivatives 715

Coenzyme A was discovered by

Fritz A. Lipmann (1899–1986).

He also was the first to recognize its

importance in intermediary

metabolism. Lipmann was born in

Germany. To escape the Nazis, he

moved to Denmark in 1932 and to the

United States in 1939, becoming a

U.S. citizen in 1944. For his work on

coenzyme A, he received the Nobel

Prize in physiology or medicine in

1953, sharing it with Hans Krebs.

The carbonyl carbon of a thioester is more susceptible to nucleophilic attack than is
the carbonyl carbon of an oxygen ester because there is less electron delocalization
onto the carbonyl oxygen when Y is S than when Y is O. There is less electron delo-
calization because there is less overlap between the 3porbital of sulfur and the 2por-
bital of carbon, compared with the amount of overlap between the 2porbital of oxygen
and the 2porbital of carbon (Section 17.2). In addition, a thiolate ion is a weaker base
and therefore a better leaving group than an alkoxide ion.

The thiol used in biological systems for the formation of thioesters is coenzyme A.
The compound is written “CoASH”to emphasize that the thiol group is the reactive
part of the molecule.

The first step in converting a carboxylic acid into a thioester is to convert the carboxylic
acid into an acyl adenylate. The acyl adenylate then reacts with CoASH to form the
thioester. The most common thioester in cells is acetyl-CoA.

Acetylcholine, an ester, is one example of a carboxylic acid derivative that cells
synthesize using acetyl-CoA. Acetylcholine is a neurotransmitter—a compound that
transmits nerve impulses across the synapses between nerve cells.

It is believed that one way genes are activated is by amide formation between acetyl-CoA
and a lysine residue (an amine) of a DNA-bound protein.

acetyl-CoA choline

CH 3 SCoA

CH 3

CH 3

+

+

CH 3

CH 3

+ HOCH 2 CH 2 NCH 3

acetylcholine

CH 3 OCH 2 CH 2 NCH 3 + CoASH

enzyme

C

O

C

O

coenzyme A

CoASH

HS CH 2 CH 2 NHCCH 2 CH 2 NHCCH CCH 2 O

O

OH

O

CH 3

CH 3

2 −O

3 PO OH

O

O−

P

O

O

O−O

P O

NH 2

N

N N

N

C

YR

O

RCCH 3 CH 2 SH

pKa = 10.5 pKa = 15.9

CH 3 CH 2 OH

YR

O

−

R +

+

CH 3 O

ATP

acetyl-CoA

−OO

O O

O−

P

O−

P

O CH 3 O

O O

C

O−

pyrophosphate

P

Ad

O

Ad

O−

− P +

CH 3 SCoA

AMP

+

enzyme CoASH

C

O

C

O

CH 3 SCoA

CH 2 CH 2 CH 2 CH 2 NH 2

CH NH

CH 2 CH 2 CH 2 CH 2 NH 2 CH 3

CH NH

+ + CoASH

a lysine residue an amide

enzyme

C

O

C

O

C

C

O

O