Structure/function relationships in the inhibition of thimet oligopeptidase by carboxyphenylpropyl‐peptides
- 9 December 1991
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 294 (3), 183-186
- https://doi.org/10.1016/0014-5793(91)80664-o
Abstract
Some novel N-[1(RS)-carboxy-3-phenylpropyl]tripeptide p-aminobenzoates have been synthesised as inhibitors of thimet oligopeptidase (EC 3.4.24.15). These compounds are considered to bind as substrate analogues with the Cpp group in S1 and the peptide portion in the S′ sites. The most potent inhibitor is Cpp-Ala-Pro-Phe-pAb, which has a K1 = 7 nM. Substitution of Gly for Ala at P1′ leads to weaker binding which can be ascribed to increased rotational freedom. Good substrates often have Pro at P2′ and Pro is favoured over Ala at this position in the inhibitors, too. When P2′ is Pro, Phe is preferred over Tyr and Trp in P3′. The p-aminobenzoate group makes an important contribution to the binding, probably by forming a salt bridge, and removal of the C-terminal negative charge results in much less potent inhibitorsKeywords
This publication has 17 references indexed in Scilit:
- Inhibition of Clostridium histolyticum collagenases by phosphonamide peptide inhibitorsEuropean Journal of Biochemistry, 1990
- An alternative quenched fluorescence substrate for Pz-peptidaseAnalytical Biochemistry, 1990
- Substrate-related potent inhibitors of brain metalloendopeptidaseBiochemistry, 1988
- Soluble Metalloendopeptidase from Rat Brain: Action on Enkephalin-Containing Peptides and Other Bioactive Peptides*Endocrinology, 1985
- Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by x-ray crystallography: a novel class of transition-state analogs for zinc peptidasesBiochemistry, 1984
- A synthetic approach to peptides of o- and p-aminobenzoic acidsAustralian Journal of Chemistry, 1983
- Inhibition of thermolysin by N-carboxymethyl dipeptidesBiochemical and Biophysical Research Communications, 1981
- Inhibition of thermolysin and carboxypeptidase A by phosphoramidatesBiochemistry, 1979
- Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitorsBiochimica et Biophysica Acta (BBA) - Enzymology, 1969
- On the size of the active site in proteases. I. PapainBiochemical and Biophysical Research Communications, 1967