Solid-phase synthesis of human osteocalcin by using a gamma-carboxyglutamic acid derivative

Human osteocalcin, also called bone Gla protein (BGP), consisting of 49 amino acids with two or three gamma-carboxyglutamate residues, was chemically synthesized for the first time by a novel solid-phase peptide synthesis. An L-enantiomer of N-tert-butyloxycarbonyl-gamma,gamma'-dicyclohexyl-gamma-carboxyglutamic acid was designed, prepared and utilized as a monomeric compound and proven to be useful for the solid-phase peptide synthesis of human osteocalcin. The synthesis and optical resolution of the gamma-carboxyglutamic acid (Gla) derivative are first described, followed by the synthesis and characterization of Gla17-human osteocalcin.