Sk. Singh et al., Synthetic peptides as inactivators of multimeric enzymes: inhibition of Plasmodium falciparum triosephosphate isomerase by interface peptides, FEBS LETTER, 501(1), 2001, pp. 19-23
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.