Introduction to Human Nutrition

The Vitamins 151

glutamate chelates calcium ions, and so permits the
binding of the blood clotting proteins to lipid mem-
branes. In vitamin K defi ciency, or in the presence of
an antagonist such as warfarin, an abnormal precur-
sor of prothrombin (preprothrombin) containing
little or no γ-carboxyglutamate is released into the
circulation. Preprothrombin cannot chelate calcium
or bind to phospholipid membranes, and so is unable
to initiate blood clotting. Preprothrombin is some-
times known as PIVKA: the protein induced by
vitamin K absence.

Other vitamin K-dependent proteins
It has long been known that treatment of pregnant
women with warfarin or other anticoagulants can
lead to bone abnormalities in the child: the fetal war-
farin syndrome. Two proteins in bone matrix contain
γ-carboxyglutamate: osteocalcin and a less well char-

acterized protein simply known as bone matrix Gla

protein. Osteocalcin is interesting in that as well as γ-

carboxyglutamate, it also contains hydroxyproline, so

its synthesis is dependent on both vitamins K and C;

in addition, its synthesis is induced by vitamin D, and

the release into the circulation of osteocalcin provides

a sensitive index of vitamin D action. It constitutes

some 1–2% of total bone protein, and modifi es the

crystallization of bone mineral. The matrix Gla

protein is found in a variety of tissues, and acts to

prevent mineralization of soft connective tissue.

The fetal warfarin syndrome involves neurological

as well as bone abnormalities. The vitamin K-

dependent carboxylase is expressed in different brain

regions at different times during embryological devel-

opment, and the product of the growth arrest-specifi c

gene 6 (Gas6) is a Gla-containing growth factor

that is important in the regulation of growth and

OH

OH

CH 3

H 2 C COO–

CH 2

NH HC C O

HC COO–

CH 2

NH HC C O

CHCOO–

CH 2

HN CHC O

• OOC

R

Glutamate residue Glutamate carbanion γ-Carboxyglutamate residue

CO 2

Nonenzymic

O 2

Vitamin K

epoxidase

O

O

CH 3

R

O

Vitamin K hydroquinone Vitamin K epoxide

O

O

CH 3

R

Vitamin K quinone

Sulphydryl

Disulphide

Vitamin K epoxide

reductase

Disulphide

Sulphydryl

Vitamin K quinone

reductase

NADPH

quinone

reductase

NADP+

Figure 8.7 Role of vitamin K in the carboxylation of glutamate. Vitamin K epoxidase (EC 1.14.99.20), warfarin-sensitive epoxide/quinone reduc-
tase (EC 1.1.4.1), warfarin-insensitive quinone reductase (EC 1.1.4.2).