Metalloform-selective inhibitors of Escherichia coli methionine aminopeptidase and X-ray structure of a Mn(II)-form enzyme complexed with an inhibitor

Qizhuang Ye, Sheng Xue Xie, Min Huang, Wei Jun Huang, Jing Ping Lu, Ze Qiang Ma

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Methionine aminopeptidase (MetAP) enzymes require a divalent metal ion such as Mn(II), Fe(II), Co(II), Ni(II), or Zn(II) for its removal of the N-terminal methionine from newly synthesized proteins, but it is not certain which of these ions is most important in vivo. Metalloform-selective MetAP inhibitors could be valuable for defining which metals are physiologically relevant for MetAP activation and could serve as leads for development of new therapeutic agents. We have screened a library of 43736 small drug-like molecules against Escherichia coli MetAP and identified two groups of potent and highly metalloform-selective inhibitors of the Co(II)-form, and of the Mn(II)-form, of this enzyme. Compound 1 is 790-fold more selective for the Co(II)-form, while compound 4 is over 640-fold more potent toward the Mn(II)-form. The X-ray structure of a di-Mn(II) form of E. coli MetAP complexed with the Mn(II)-form-selective compound 4 was obtained, and it shows that the inhibitor interacts with both Mn(II) ions through the two oxygen atoms of its free carboxylate group. The preferential coordination of the hard (oxygen) donors to Mn(II) may contribute to its superb selectivity toward the Mn(II)-form.

Original languageEnglish (US)
Pages (from-to)13940-13941
Number of pages2
JournalJournal of the American Chemical Society
Volume126
Issue number43
DOIs
StatePublished - Nov 3 2004
Externally publishedYes

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Aminopeptidases
Methionine
Escherichia coli
Enzymes
X-Rays
X rays
Oxygen
Ions
Corrosion inhibitors
Metal ions
Chemical activation
Proteins
Atoms
Molecules
Metals
aminopeptidase X
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Metalloform-selective inhibitors of Escherichia coli methionine aminopeptidase and X-ray structure of a Mn(II)-form enzyme complexed with an inhibitor. / Ye, Qizhuang; Xie, Sheng Xue; Huang, Min; Huang, Wei Jun; Lu, Jing Ping; Ma, Ze Qiang.

In: Journal of the American Chemical Society, Vol. 126, No. 43, 03.11.2004, p. 13940-13941.

Research output: Contribution to journalArticle

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