Synthesis of peptide analogs of prothrombin precursor sequence 5-9. Substrate specificity of vitamin K dependent carboxylase

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Abstract
Analogs (35) of Phe-Leu-Glu-Glu-Leu, the pentapeptide sequences 5-9 of bovine prothrombin precursor, were synthesized and assayed as potential substrates or inhibitors of rat liver vitamin K dependent carboxylase. Carboxylation of substrate was determined by measuring the incorporation of 14C-labeled bicarbonate into product. Changes in substrate carboxylation produced by changing peptide chain length, amino acid chirality or the distance separating the peptide chain backbone from the carboxyl group were measured. The carboxylase carboxylates L-glutamic acid residues and does not carboxylate L-aspartic acid, L-homoglutamic acid, glutamine or D-glutamic acid residues; tri- through pentapeptides are better substrates than mono- or bis(amino acid) derivatives, and hydrophobic groups added to the N-terminus can produce better substrates for the enzyme. None of the synthetic substrates is carboxylated as effectively as the endogenous protein substrates for the enzyme. The effect of structure on additional parameters affecting carboxylation is discussed.

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