Synthetic peptides as inactivators of multimeric enzymes: inhibition of Plasmodium falciparum triosephosphate isomerase by interface peptides

Synthetic peptides corresponding to two distinct segments of the subunit in terface of the homodimeric enzyme triosephosphate isomerase (residues 9-18, ANWKCNGTLE, peptide I; residues 68-79, KFGNGSYTGEVS, peptide II) from Plas modium falciparum (PfTIM) have been investigated for their ability to act a s inhibitors by interfering with the quaternary structure of the enzyme. An analog of peptide II containing cysteine at the site corresponding to posi tion 74 and tyrosine at position 69 in the protein sequence KYGNGSCTGEVGS ( peptide III) was also investigated. A substantial fall in enzyme activity w as observed following incubation of the enzyme with peptide II, whereas pep tide I did not show any appreciable inhibition. The inhibitory effect was m ore pronounced on two mutants of PfTIM (Y74C and Y74G), both of which have reduced stability compared to the wild-type protein due to an interface cav ity, The IC50 value determined for peptide II is in the range of 0.6-0.8 mu M. This study suggests that interface peptides of oligomeric enzymes can be used to inhibit dimeric enzymes by disrupting their native multimeric stat es and may provide lead structures for potential inhibitor design. (C) 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.