Kinetics and mechanism of the facile cyclization of histidyl-prolineamide to cyclo (His-Pro) in aqueous solution and the competitive influence of human plasma

J Pharm Pharmacol. 1990 Jan;42(1):7-12. doi: 10.1111/j.2042-7158.1990.tb05340.x.

Abstract

A crucial point in the biosynthesis of cyclo (His-Pro), an endogenous and biologically active cyclic dipeptide, is the spontaneous cyclization of its precursor L-histidyl-L-prolineamide (His-ProNH2). In this study the kinetics and mechanism of the cyclization process has been investigated. His-ProNH2 was found to be converted quantitatively to cyclo(His-Pro) in aqueous solution at pH 2-10 and 37 degrees C, the rate of cyclization being maximal at pH 6-7. Buffer substances such as phosphate (pH 6-7.4) were found to catalyse the cyclization. The bell-shaped pH-rate profile observed was accounted for by assuming spontaneous and specific acid- and base-catalysed reactions of the His-ProNH2 species in which the imidazole group is protonated and the primary amino group unprotonated. The much more rapid rate of cyclization of His-ProNH2 (t1/2 of 140 min at pH 6-7 and 37 degrees C) relative to other proline-containing di- and tripeptides studied was suggested to be due to an intramolecular general acid catalytic effect by the protonated imidazole group. In the presence of human plasma enzymatic hydrolysis of His-ProNH2 competed with the cyclization and predominated greatly at 80% plasma concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Buffers
  • Chromatography, High Pressure Liquid
  • Cyclization
  • Drug Stability
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Peptides, Cyclic / blood
  • Peptides, Cyclic / chemical synthesis*
  • Piperazines / blood
  • Piperazines / chemical synthesis*
  • Solutions

Substances

  • Buffers
  • Peptides, Cyclic
  • Piperazines
  • Solutions
  • histidyl-proline diketopiperazine