Biological Ligands for Metal Ions - Biological Inorganic Chemistry - page 71

A number of proteins of the blood clotting (coagulation) cascade (including prothrombin, and a number of
other clotting factors) undergo post-translational modification 1 in a reaction catalysed by a vitamin K-dependent
carboxylase, which transforms specific Glu residues into -carboxyglutamic acid, Gla ( Fig. 4.1 ) . In the reaction

( Fig. 4.2 ) , the dihydroquinone (reduced) form of vitamin K, KH 2 , is oxidised to the epoxide form, KO, by O 2 .The

g

FIGURE 4.2 The vitamin K cycle as it functions in protein glutamyl carboxylation reaction. The conversion of protein-bound glutamic acid
into g -carboxyglutamic acid is catalysed by a carboxylase. During the carboxylation reaction vitamin K hydroquinone (KH 2 ) is converted to
vitamin K epoxide (KO). X e (SH) 2 and X e S 2 represent, respectively, the reduced and oxidised forms of thioredoxin. The NADH-dependent
and dithiol-dependent vitamin K reductases are different enzymes. Both the dithiol-dependent K- and KO-reductases are inhibited by
dicoumarol (I) and warfarin (II).

epoxide, KO, is then converted back to the KH 2 form by two reductases, which require dithiols, like thioredoxin,
as cofactor.
g -Carboxyglutamic acid is a much better chelator of Ca 2 þ than glutamate itself, enabling prothrombin to bind

Ca 2 þ , which anchors it to the membranes of blood platelets released after injury. This then positions prothrombin
in close proximity to other proteases of the blood clotting cascade, initiating the sequence of events which leads to
clot formation. Both of the dithiol-dependent K- and KO-reductases are inhibited by dicoumarol (I) and warfarin

1. Enzyme-catalysed modification of the protein after the protein has been released from the ribosome (the protein synthesis assembly
machinery).