Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

Omonike Olaleye; Tirumalai R. Raghunand; Shridhar Bhat; Jian He; Sandeep Tyagi; Gyanu Lamichhane; Peihua Gu; Jiangbing Zhou; Ying Zhang; Jacques Grosset; William R. Bishai; Jun O. Liu

doi:10.1016/j.chembiol.2009.12.014

Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

Omonike Olaleye, Tirumalai R. Raghunand, Shridhar Bhat, Jian He, Sandeep Tyagi, Gyanu Lamichhane, Peihua Gu, Jiangbing Zhou, Ying Zhang, Jacques Grosset, William R. Bishai, Jun O. Liu

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

Summary: Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.

Original language	English (US)
Pages (from-to)	86-97
Number of pages	12
Journal	Chemistry and Biology
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.chembiol.2009.12.014
State	Published - Jan 29 2010

Keywords

CHEMBIO
HUMDISEASE
MICROBIO

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Molecular Biology
Clinical Biochemistry
Molecular Medicine
Pharmacology

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10.1016/j.chembiol.2009.12.014

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title = "Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets",

abstract = "Summary: Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.",

keywords = "CHEMBIO, HUMDISEASE, MICROBIO",

author = "Omonike Olaleye and Raghunand, {Tirumalai R.} and Shridhar Bhat and Jian He and Sandeep Tyagi and Gyanu Lamichhane and Peihua Gu and Jiangbing Zhou and Ying Zhang and Jacques Grosset and Bishai, {William R.} and Liu, {Jun O.}",

note = "Funding Information: We thank Curtis Chong, Keechung Han, Norman Morrison, Nisheeth Agarwal, and Deborah Geiman for helpful discussions. We thank ASDI Inc. for the provision of the chemical compound library. This work was supported in part by the National Institutes of Health (grants AI36973, AI37856, AI43846, and AI30036). O.O. was supported by the UNCF ∗ Merck Graduate Science Research Dissertation Fellowship and National Aeronautics Space Administration Harriett Jenkins Pre-Doctoral Fellowship. ",

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language = "English (US)",

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T1 - Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

AU - Olaleye, Omonike

AU - Raghunand, Tirumalai R.

AU - Bhat, Shridhar

AU - He, Jian

AU - Tyagi, Sandeep

AU - Lamichhane, Gyanu

AU - Gu, Peihua

AU - Zhou, Jiangbing

AU - Zhang, Ying

AU - Grosset, Jacques

AU - Bishai, William R.

AU - Liu, Jun O.

N1 - Funding Information: We thank Curtis Chong, Keechung Han, Norman Morrison, Nisheeth Agarwal, and Deborah Geiman for helpful discussions. We thank ASDI Inc. for the provision of the chemical compound library. This work was supported in part by the National Institutes of Health (grants AI36973, AI37856, AI43846, and AI30036). O.O. was supported by the UNCF ∗ Merck Graduate Science Research Dissertation Fellowship and National Aeronautics Space Administration Harriett Jenkins Pre-Doctoral Fellowship.

PY - 2010/1/29

Y1 - 2010/1/29

N2 - Summary: Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.

AB - Summary: Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.

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Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

Abstract

Keywords

ASJC Scopus subject areas

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