Organic Chemistry

Section 25.9 Vitamin KH 2 :Vitamin K 1069

Vitamin is required by the enzyme

that catalyzes the carboxylation of the

of a glutamate side chain in a

protein.

G-carbon

proteins involved in blood clotting all have several glutamates near their N-terminal KH 2
ends. For example, prothrombin has glutamates at positions 7, 8, 15, 17, 20, 21, 26, 27,
30, and 33.

The mechanism for the vitamin –catalyzed carboxylation of glutamate had
puzzled chemists because the that must be removed from glutamate before it
can attack is not very acidic. The mechanism, therefore, must involve the creation
of a strong base. The following mechanism has been proposed by Paul Dowd: The vi-
tamin loses a proton from a phenolic OH group, and the base that is thereby formed at-
tacks molecular oxygen. A dioxetane is formed and then collapses to give a vitamin K
base that is strong enough to remove a proton from the of glutamate. The
glutamate carbanion attacks to form and the protonated vit-
amin K base (a hydrate) loses water, forming vitamin K epoxide.

CO 2 g-carboxyglutamate,

g-carbon

CO 2

g-proton

KH 2 Paul Dowd (1936–1996)was born in

Brockton, Massachusetts. He did his

undergraduate work at Harvard

University and received a Ph.D. from

Columbia University. He was a

professor of chemistry at Harvard

University and was a professor of

chemistry from 1970 to 1996 at the

University of Pittsburgh.

O−

NH CH

O

C

enzyme

vitamin KH 2

CH 2 CO^2

CH 2

O−O−

OOC C

NH CH

O

C

Ca^2 +

CH 2

CH

CO

O−

Ca^2 +

O−

OOC C

NH CH

O

C

CH 2

CH

glutamate side chain -carboxyglutamate side chain
calcium complex

B−

O

OH

R

OO

O−

OH

R

OO−

O

HO

R

mechanism for the vitamin KH 2 -dependent carboxylation of glutamate

O

O

O−

HO

R

a dioxetane

H B H

O O

OCO

O

O−O−

CCO

+ +

−H 2 O

O−

O

HO

R

NHCHC

CH 2

H CH

COO−

O

NHCHC

CH 2

−CH

COO−

O

NHCHC

CH 2

CH

O

OH

O

HO

R

O

O

O

R

vitamin K base

vitamin K epoxide

-carboxyglutamate