Two methionine aminopeptidases from Acinetobacter baumannii are functional enzymes

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Yuan, Hai¹  Chai, Sergio C.¹  Lam, Christopher K.²  Xu, H. Howard²  Ye, Qi-Zhuang¹ 

[1] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[2] Calif State Univ Los Angeles, Dept Biol Sci, Los Angeles, CA 90032 USA

关键词: Metalloenzyme;    Drug resistance;    Gram-negative bacteria;    Drug discovery;    Antibiotics;    Metal activation;   

DOI  :  10.1016/j.bmcl.2011.03.116

来源: Elsevier

【 摘 要 】

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) approximate to 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. (C) 2011 Elsevier Ltd. All rights reserved.

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