Crystal Structures of Staphylococcus aureus Methionine Aminopeptidase Complexed with Keto Heterocycle and Aminoketone Inhibitors Reveal the Formation of a Tetrahedral Intermediate.

Abstract

Chem. 2002, 67, 3637-3642) suggested that structures attributed by us to 4a, 4d, 7a, and 7d are incorrect. Our own re-investigation led us to conclude that compounds 4a, 4d, 7a, and 7d have aza-bicyclo[3.2.2]nonane structures as depicted in the accompanying graphic. These revised structures have been confirmed by NMR and X-ray analysis.

Inhibition of Monometalated Methionine Aminopeptidase: Inhibitor Discovery and Crystallographic Analysis

“…Structures of dimetalated and trimetalated MetAP in complex with non-peptidic inhibitors are abundant in literature 11,12,34,39,40 . When a high metal concentration is used in inhibitor screening, the condition favors formation of dimetalated MetAP, and the screening tends to identify inhibitors that require extra metal ions for affinity.…”

Structural analysis of inhibition of E. coli methionine aminopeptidase: implication of loop adaptability in selective inhibition of bacterial enzymes

“…Fumagillin, a natural product, and its analogues are a unique class of MetAP inhibitors that covalently modify a conserved histidine residue at the active site (H79 of E. coli MetAP, and the equivalent H231 of human type II MetAP) [ 9 , 15 , 16 ]. Several classes of non-peptidic and reversible MetAP inhibitors have been identified recently, such as furancarboxylic acids [ 17 , 18 ], thiabendazole and other thiazole-containing compounds [ 17 , 19 - 21 ], triazole-based derivatives [ 22 - 24 ], and sulfonamides [ 25 , 26 ]. However, structural analysis of these nonpeptidic inhibitors in complex with MetAP showed that inhibition by many of the thiazole and triazole-containing compounds and sulfonamides is metal-mediated, and they bind to the active site of enzyme through a divalent metal ion with one of the conserved active site histidines (most with H97, and some with H181; both are E. coli MetAP numbering) [ 19 , 21 , 25 ].…”

“…Several classes of non-peptidic and reversible MetAP inhibitors have been identified recently, such as furancarboxylic acids [ 17 , 18 ], thiabendazole and other thiazole-containing compounds [ 17 , 19 - 21 ], triazole-based derivatives [ 22 - 24 ], and sulfonamides [ 25 , 26 ]. However, structural analysis of these nonpeptidic inhibitors in complex with MetAP showed that inhibition by many of the thiazole and triazole-containing compounds and sulfonamides is metal-mediated, and they bind to the active site of enzyme through a divalent metal ion with one of the conserved active site histidines (most with H97, and some with H181; both are E. coli MetAP numbering) [ 19 , 21 , 25 ]. It has been pointed out that formation of such complexes may be an artefact during crystallization or in in vitro assays using high metal concentrations [ 14 , 19 , 27 ], and whether there are enough free metal ions available inside cells to form such inhibitor-enzyme complexes is a question.…”

Selective targeting of the conserved active site cysteine of Mycobacterium tuberculosis methionine aminopeptidase with electrophilic reagents

“…Similarly, inhibition of all three human MetAPs was beneficial in killing cancer cells . Several studies have been directed at finding inhibitors of these enzymes . However, owing to the similarity in the active sites among all MetAPs, achieving selectivity with small molecules between the type I and type II enzymes is difficult .…”