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Title: Catalysis and Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidase

Abstract

Methionine aminopeptidase (MetAP) carries out an important cotranslational N-terminal methionine excision of nascent proteins and represents a potential target to develop antibacterial and antitubercular drugs. We cloned one of the two MetAPs in Mycobacterium tuberculosis (MtMetAP1c from the mapB gene) and purified it to homogeneity as an apoenzyme. Its activity required a divalent metal ion, and Co(II), Ni(II), Mn(II), and Fe(II) were among activators of the enzyme. Co(II) and Fe(II) had the tightest binding, while Ni(II) was the most efficient cofactor for the catalysis. MtMetAP1c was also functional in E. coli cells because a plasmid-expressed MtMetAP1c complemented the essential function of MetAP in E. coli and supported the cell growth. A set of potent MtMetAP1c inhibitors were identified, and they showed high selectivity toward the Fe(II)-form, the Mn(II)-form, or the Co(II) and Ni(II) forms of the enzyme, respectively. These metalloform selective inhibitors were used to assign the metalloform of the cellular MtMetAP1c. The fact that only the Fe(II)-form selective inhibitors inhibited the cellular MtMetAP1c activity and inhibited the MtMetAP1c-complemented cell growth suggests that Fe(II) is the native metal used by MtMetAP1c in an E. coli cellular environment. Finally, X-ray structures of MtMetAP1c in complex with three metalloform-selective inhibitors were analyzed,more » which showed different binding modes and different interactions with metal ions and active site residues.« less

Authors:
; ;  [1]
  1. Indiana-Med
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1002669
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 53; Journal Issue: (3) ; 02, 2010; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AMINOPEPTIDASES; CATALYSIS; FUNCTIONALS; METHIONINE; MYCOBACTERIUM TUBERCULOSIS; PROTEINS; RESIDUES; TARGETS

Citation Formats

Lu, Jing-Ping, Chai, Sergio C, and Ye, Qi-Zhuang. Catalysis and Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidase. United States: N. p., 2010. Web. doi:10.1021/jm901624n.
Lu, Jing-Ping, Chai, Sergio C, & Ye, Qi-Zhuang. Catalysis and Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidase. United States. https://doi.org/10.1021/jm901624n
Lu, Jing-Ping, Chai, Sergio C, and Ye, Qi-Zhuang. 2010. "Catalysis and Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidase". United States. https://doi.org/10.1021/jm901624n.
@article{osti_1002669,
title = {Catalysis and Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidase},
author = {Lu, Jing-Ping and Chai, Sergio C and Ye, Qi-Zhuang},
abstractNote = {Methionine aminopeptidase (MetAP) carries out an important cotranslational N-terminal methionine excision of nascent proteins and represents a potential target to develop antibacterial and antitubercular drugs. We cloned one of the two MetAPs in Mycobacterium tuberculosis (MtMetAP1c from the mapB gene) and purified it to homogeneity as an apoenzyme. Its activity required a divalent metal ion, and Co(II), Ni(II), Mn(II), and Fe(II) were among activators of the enzyme. Co(II) and Fe(II) had the tightest binding, while Ni(II) was the most efficient cofactor for the catalysis. MtMetAP1c was also functional in E. coli cells because a plasmid-expressed MtMetAP1c complemented the essential function of MetAP in E. coli and supported the cell growth. A set of potent MtMetAP1c inhibitors were identified, and they showed high selectivity toward the Fe(II)-form, the Mn(II)-form, or the Co(II) and Ni(II) forms of the enzyme, respectively. These metalloform selective inhibitors were used to assign the metalloform of the cellular MtMetAP1c. The fact that only the Fe(II)-form selective inhibitors inhibited the cellular MtMetAP1c activity and inhibited the MtMetAP1c-complemented cell growth suggests that Fe(II) is the native metal used by MtMetAP1c in an E. coli cellular environment. Finally, X-ray structures of MtMetAP1c in complex with three metalloform-selective inhibitors were analyzed, which showed different binding modes and different interactions with metal ions and active site residues.},
doi = {10.1021/jm901624n},
url = {https://www.osti.gov/biblio/1002669}, journal = {J. Med. Chem.},
issn = {0022-2623},
number = (3) ; 02, 2010,
volume = 53,
place = {United States},
year = {Tue Sep 07 00:00:00 EDT 2010},
month = {Tue Sep 07 00:00:00 EDT 2010}
}