Proceedings of the National Academy of Sciences · 1974 · 751 citations · 13 references
Life SciencesBiochemistryCalcium HomeostasisClinical BiochemistryProtein BiochemistryAmino Acid CompositionPlasma ProteinsVitamin BiochemistryVitamin K DeficiencyVitamin PhysiologyAmino Acid Composition AnalysisCalcium Dependence In CoagulationCoagulationElectrophoretic MobilityNuclear Magnetic Resonance SpectroscopyPeptide Mass SpectrometryProthrombin ActivationVitamin K Antagonists
The tetrapeptide (residues 6–9) isolated from the NH₂‑terminal Ca²⁺‑binding region of prothrombin contains two γ‑carboxyglutamic acid residues that confer the Ca²⁺‑binding ability required for activation. NMR and mass‑spectrometry analysis showed that the peptide’s unusually high electrophoretic mobility is due to these two γ‑carboxyglutamic acids, and that dicoumarol‑induced abnormal prothrombin lacks them, preventing Ca²⁺ binding and rendering it nonfunctional in coagulation.
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.
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