Two methionine aminopeptidases from Acinetobacter baumannii are functional enzymes

Hai Yuan, Sergio C. Chai, Christopher K. Lam, H. Howard Xu, Qi Zhuang Ye

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Drug resistance in Gram-negative bacteria, such as Acinetobacter baumannii, is emerging as a significant healthcare problem. New antibiotics with a novel mechanism of action are urgently needed to overcome the drug resistance. Methionine aminopeptidase (MetAP) carries out an essential cotranslational methionine excision in many bacteria and is a potential target to develop such novel antibiotics. Two putative MetAP genes were identified in A. baumannii genome, but whether they actually function as MetAP enzymes was not known. Therefore, we established an efficient E. coli expression system for their production as soluble and metal-free proteins for biochemical characterization. We demonstrated that both could carry out the metal-dependent catalysis and could be activated by divalent metal ions with the order Fe(II) ≈ Ni(II) > Co(II) > Mn(II) for both. By using a set of metalloform-selective inhibitors discovered on other MetAP enzymes, potency and metalloform selectivity on the A. baumannii MetAP proteins were observed. The similarity of their catalysis and inhibition to other MetAP enzymes confirmed that both may function as competent MetAP enzymes in A. baumannii and either or both may serve as the potential drug target.

Original languageEnglish (US)
Pages (from-to)3395-3398
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2011

Keywords

  • Antibiotics
  • Drug discovery
  • Drug resistance
  • Gram-negative bacteria
  • Metal activation
  • Metalloenzyme

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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