Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

Catherine T. Chaton; Emily S. Rodriguez; Robert W. Reed; Jian Li; Cameron W. Kenner; Konstantin V. Korotkov

doi:10.1038/s41598-019-56722-2

Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

Catherine T. Chaton, Emily S. Rodriguez, Robert W. Reed, Jian Li, Cameron W. Kenner, Konstantin V. Korotkov

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

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Abstract

Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

Original language	English
Article number	20267
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-56722-2
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

The work in this study was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health grants P20GM103486 and P30GM110787 to K.V.K. E.S.R. was supported by the National Science Foundation Research Experiences for Undergraduates (REU) grant 1358627. E.S.R. is the American Chemical Society Scholar. C.W.K. was supported by a Howard Hughes Medical Institute undergraduate science education grant to Georgetown College and the Georgetown College Science Honors Program. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (P41GM103393). Use of SER-CAT is supported by its member institutions (see www.ser-cat.org/members.html), and equipment grants (S10_RR25528 and S10_RR028976) from the National Institutes of Health. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, contract W-31-109-Eng-38. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Funders	Funder number
DOE Office of Biological and Environmental Research	S10_RR028976, S10_RR25528
Georgetown College
Georgetown College Science Honors Program
National Science Foundation Research Experiences for Undergraduates
Office of Basic Energy Sciences
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China	1358627
U.S. Department of Energy Chinese Academy of Sciences Guangzhou Municipal Science and Technology Project Oak Ridge National Laboratory Extreme Science and Engineering Discovery Environment National Science Foundation National Energy Research Scientific Computing Center National Natural Science Foundation of China
National Institutes of Health (NIH)
Howard Hughes Medical Institute
U.S. Department of Energy Oak Ridge National Laboratory U.S. Department of Energy National Science Foundation National Energy Research Scientific Computing Center	W-31-109-Eng-38
U.S. Department of Energy Oak Ridge National Laboratory U.S. Department of Energy National Science Foundation National Energy Research Scientific Computing Center
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	P30GM110787, P20GM103486, P41GM103393
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences
National Science Foundation Office of International Science and Engineering
ReumaNederland

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title = "Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site",

abstract = "Mycobacterium tuberculosis is the cause of the world{\textquoteright}s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.",

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AU - Chaton, Catherine T.

AU - Rodriguez, Emily S.

AU - Reed, Robert W.

AU - Li, Jian

AU - Kenner, Cameron W.

AU - Korotkov, Konstantin V.

PY - 2019/12/1

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N2 - Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

AB - Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

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Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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