Vitamin K dependent modifications of glutamic acid residues in prothrombin.

A tetrapeptide, residues 6 to 9 in normal prothrombin, was isolated from the NH(2)-terminal, Ca(2+)-binding part of normal prothrombin. The electrophoretic mobility of the peptide was too high to be explained entirely by its amino-acid composition. According to (1)H nuclear magnetic resonance spectroscopy and mass spectrometry, the peptide contained two residues of modified glutamic acid, gamma-carboxyglutamic acid (3-amino-1,1,3-propanetricarboxylic acid), a hitherto unidentified amino acid. This amino acid gives normal prothrombin the Ca(2+)-binding ability that is necessary for its activation. Observations indicate that abnormal prothrombin, induced by the vitamin K antagonist, dicoumarol, lacks these modified glutamic acid residues and that this is the reason why abnormal prothrombin does not bind Ca(2+) and is nonfunctioning in blood coagulation.