Hydrolytic Cleavage of Pyroglutamyl-Peptide Bond. II. Effects of Amino Acid Residue Neighboring the pGlu Moiety

Abstract

We studied the susceptibility of the pyrrolidone moiety and the pyroglutamyl-peptide bond at pGlu-X-Ala-Phe-OH (X=Gly, Ala, Tyr, Ile, Pro, His, Lys, Arg, Thr, Ser, Asp, Glu and Trp) to 1 N HCl or 2 M trifluoromethanesulfonic acid at 60°C. Here we describe the rates of the cleavage reaction of the pGlu-X bond, the pyrrolidone ring-opening reaction of the pGlu moiety and the hydrolysate accumulation. The rank order of the susceptibility rates of the cleavage reactions was Ser>Pro, Gly>Arg, Ala, Glu, Thr, Asp>His, Lys>Trp, Tyr, Ile, and that of the ring-opening reaction was Ile>Tyr, Trp>Arg, His, Lys, Asp>Glu>Ala>Pro, Gly>Ser>Thr. The rank order of the half-lives of the model peptides was Pro>Arg, Lys, Ile>His, Glu>Ala, Tyr>Asp>Gly>Ser>Thr. The results indicated that a bulky and sterically hindered side chain of the amino acid residue neighboring the pGlu moiety favors the ring-opening reaction, and retards the decomposition on acid hydrolysis and the cleavage reaction. Thus, the ring-opening and the cleavage reactions were greatly affected by the amino acid residue neighboring the pGlu moiety in the hydrolysis of pGlu-peptides.