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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’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.

Authors:
 [1];  [2];  [1];  [3];  [4];  [1]
+ Show Author Affiliations
  1. Univ. of Kentucky, Lexington, KY (United States)
  2. The Ohio State Univ., Columbus, OH (United States); Univ. of Kentucky, Lexington, KY (United States)
  3. Gannan Medical Univ., Jiangxi (China); Univ. of Kentucky, Lexington, KY (United States)
  4. Georgetown College, KY (United States); Univ. of Kentucky, Lexington, KY (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health; National Science Foundation Research Experiences for Undergraduates (REU)
OSTI Identifier:
1596134
Grant/Contract Number:  
AC02-76SF00515; P41GM103393; W-31-109-Eng-38; S10_RR25528; S10_RR028976; P20GM103486; P30GM110787; 1358627
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; biochemistry; enzymes; structural biology; transferases; X-ray crystallography

Citation Formats

Chaton, Catherine T., Rodriguez, Emily S., Reed, Robert W., Li, Jian, Kenner, Cameron W., and Korotkov, Konstantin V. Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site. United States: N. p., 2019. Web. doi:10.1038/s41598-019-56722-2.
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Chaton, Catherine T., Rodriguez, Emily S., Reed, Robert W., Li, Jian, Kenner, Cameron W., & Korotkov, Konstantin V. Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site. United States. https://doi.org/10.1038/s41598-019-56722-2
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Chaton, Catherine T., Rodriguez, Emily S., Reed, Robert W., Li, Jian, Kenner, Cameron W., and Korotkov, Konstantin V. Mon . "Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site". United States. https://doi.org/10.1038/s41598-019-56722-2. https://www.osti.gov/servlets/purl/1596134.
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@article{osti_1596134,
title = {Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site},
author = {Chaton, Catherine T. and Rodriguez, Emily S. and Reed, Robert W. and Li, Jian and Kenner, Cameron W. and Korotkov, Konstantin V.},
abstractNote = {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.},
doi = {10.1038/s41598-019-56722-2},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United States},
year = {Mon Dec 30 00:00:00 EST 2019},
month = {Mon Dec 30 00:00:00 EST 2019}
}
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https://doi.org/10.1038/s41598-019-56722-2
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