582
THE ORGANIC CHEMISTRY OF INTERMEDIARY METABOLISM
with NAD
+ , since it contains an oxidizable CH–OH
function. The product is then a thioester. The
thioester is attacked by a phosphate nucleophile, and
since it contains a good leaving group, EnzS
− , the
reaction product is released from the enzyme as 1,3diphosphoglycerate.
H
O
Enz SH
EnzS
OH
H
EnzS
O
EnzS
OP
O
thioester
hemithioacetal
stepwise sequence involving thiol-containing enzyme
O
OP
phosphate
acting as
nucleophile
oxidizable
function
C
OH
H
O
P
O
O
O
H
NAD
+ NADH
If we look at the structure of 1,3-diphosphoglycerate, we can see that it is actually an anhydride, albeit a
mixed anhydride of a carboxylic acid and phosphoric
acid (see Box 7.27). Accordingly, we expect it to
be fairly reactive towards nucleophiles, and indeed it
is. It is sufficiently reactive that hydrolysis liberates
enough energy to synthesize ATP from ADP.
1,3-diphosphoglycerate is a mixed anhydride of carboxylic and phosphoric acid
(ADP)
H
OH
CH 2 OP
O
ester
OH
anhydride
(ATP)
hydrolysis liberates sufficient energy to synthesize ATP from ADP
substrate-level phosphorylation
3-phosphoglycerate
O
P
OH
OH
H
OH
CH 2 OP
O
O
O
P
OH
OH
H
OH
CH 2 OP
O
O
OR
H
HOR
POR
ATP synthesis is achieved by ADP acting as the
nucleophile towards this mixed anhydride, attacking
the P=O bond, with the carboxylate being the leaving group. Note that this reaction is favoured, whereas
the alternative possibility involving hydrolysis of the
phosphate ester does not occur. This is precisely
what we would predict knowing the different reactivities of anhydrides and esters (see Section 7.8).
This direct synthesis of ATP by a process in which
ADP acquires an additional phosphate from a suitable donor molecule is often termed substrate-level
phosphorylation, differentiating it from ATP synthesis that is achieved through oxidative phosphorylation.
After donating its phosphate group to ADP, 1,3diphosphoglycerate is converted into 3-phosphoglycerate. This reaction is followed by enzymic
modification to 2-phosphoglycerate.
CO 2 H
H
OH
CH 2 OP
CO 2 H
H
OP
CH 2 OH
3-phosphoglycerate
2-phosphoglycerate
phosphoglycerate
mutase
THE ORGANIC CHEMISTRY OF INTERMEDIARY METABOLISM
with NAD
+ , since it contains an oxidizable CH–OH
function. The product is then a thioester. The
thioester is attacked by a phosphate nucleophile, and
since it contains a good leaving group, EnzS
− , the
reaction product is released from the enzyme as 1,3diphosphoglycerate.
H
O
Enz SH
EnzS
OH
H
EnzS
O
EnzS
OP
O
thioester
hemithioacetal
stepwise sequence involving thiol-containing enzyme
O
OP
phosphate
acting as
nucleophile
oxidizable
function
C
OH
H
O
P
O
O
O
H
NAD
+ NADH
If we look at the structure of 1,3-diphosphoglycerate, we can see that it is actually an anhydride, albeit a
mixed anhydride of a carboxylic acid and phosphoric
acid (see Box 7.27). Accordingly, we expect it to
be fairly reactive towards nucleophiles, and indeed it
is. It is sufficiently reactive that hydrolysis liberates
enough energy to synthesize ATP from ADP.
1,3-diphosphoglycerate is a mixed anhydride of carboxylic and phosphoric acid
(ADP)
H
OH
CH 2 OP
O
ester
OH
anhydride
(ATP)
hydrolysis liberates sufficient energy to synthesize ATP from ADP
substrate-level phosphorylation
3-phosphoglycerate
O
P
OH
OH
H
OH
CH 2 OP
O
O
O
P
OH
OH
H
OH
CH 2 OP
O
O
OR
H
HOR
POR
ATP synthesis is achieved by ADP acting as the
nucleophile towards this mixed anhydride, attacking
the P=O bond, with the carboxylate being the leaving group. Note that this reaction is favoured, whereas
the alternative possibility involving hydrolysis of the
phosphate ester does not occur. This is precisely
what we would predict knowing the different reactivities of anhydrides and esters (see Section 7.8).
This direct synthesis of ATP by a process in which
ADP acquires an additional phosphate from a suitable donor molecule is often termed substrate-level
phosphorylation, differentiating it from ATP synthesis that is achieved through oxidative phosphorylation.
After donating its phosphate group to ADP, 1,3diphosphoglycerate is converted into 3-phosphoglycerate. This reaction is followed by enzymic
modification to 2-phosphoglycerate.
CO 2 H
H
OH
CH 2 OP
CO 2 H
H
OP
CH 2 OH
3-phosphoglycerate
2-phosphoglycerate
phosphoglycerate
mutase