Inhibition of protein kinase C by retro-inverso pseudosubstrate analogues

Biochem Biophys Res Commun. 1989 Dec 29;165(3):1382-90. doi: 10.1016/0006-291x(89)92757-5.

Abstract

A retro-inverso analogue of the pseudosubstrate sequence, Arg-Phe-Ala-Arg-Lys-Gly-Ala25-Leu-Arg-Gln-Lys-Asn-Val (1), found in the regulatory domain of all protein kinase C (PKC) subspecies was synthesized. It shows to be an inhibitor (IC50 = 31 microM) of the phosphorylation, by PKC, of [Ala9.10,Lys11.12] glycogen synthase (1-12). Its analogue in which D Ala25 is replaced by D Ser is not a PKC substrate, but a more potent inhibitor, competitive with the peptidic substrate (IC50 = 5 microM, Ki = 2 microM). Both retro-inverso peptides are highly specific for PKC versus adenosine cAMP-dependent protein kinase (PKA) and are totally stable towards proteolysis by trypsin or pronase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Chromatography, High Pressure Liquid
  • Glycogen Synthase / metabolism
  • Molecular Sequence Data
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Peptide Fragments / metabolism
  • Phosphorylation
  • Pronase / metabolism
  • Protein Kinase C / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Trypsin / metabolism

Substances

  • Oligopeptides
  • Peptide Fragments
  • Glycogen Synthase
  • Protein Kinase C
  • Trypsin
  • Pronase