Protonation states of methionine aminopeptidase and their relevance for inhibitor binding and catalytic activity

The authors have performed a computational study of different protomeric states of the methionine aminopeptidase active site using a combined quantum-mech./mol. mech. simulation approach. The aim of this study was to clarify the native protonation state of the enzyme, which is needed for the development of novel irreversible inhibitors that can possibly be used as antiangiogenic and antibiotic drugs by virtual screening and other drug design methods. The results of the simulations indicated that two protonation states are possible without disturbing the overall geometry of the active site. The authors then verified exptl. the presence of the two protonation states by studying the substrate hydrolysis and inhibitor binding reactions at different pH values and come to the conclusion that one of the protomeric states is relevant for inhibitor binding, whereas the other is relevant for substrate hydrolysis. This result has implications for the development of other inhibitors of this class of enzymes and adds a new perspective to the pharmacol. properties of the antiangiogenic drug fumagillin, which is an irreversible inhibitor of the human methionine aminopeptidase type II. [on SciFinder (R)]

Published in:
Journal of Biological Chemistry, 278, 48, 47862-47867
Other identifiers:
DAR: 4416

 Record created 2006-02-27, last modified 2018-01-27

Rate this document:

Rate this document:
(Not yet reviewed)