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

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

doi:10.1038/s41598-019-56722-2

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

Journal Article · 29 December 2019 · Scientific Reports

DOI: https://doi.org/10.1038/s41598-019-56722-2 · OSTI ID:1596134

Chaton, Catherine T. ^[1]; Rodriguez, Emily S. ^[2]; Reed, Robert W. ^[1]; Li, Jian ^[3]; Kenner, Cameron W. ^[4]; Korotkov, Konstantin V. ^[1]

Univ. of Kentucky, Lexington, KY (United States)
The Ohio State Univ., Columbus, OH (United States); Univ. of Kentucky, Lexington, KY (United States)
Gannan Medical Univ., Jiangxi (China); Univ. of Kentucky, Lexington, KY (United States)
Georgetown College, KY (United States); Univ. of Kentucky, Lexington, KY (United States)

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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; National Science Foundation Research Experiences for Undergraduates (REU); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-76SF00515; W-31109-ENG-38

OSTI ID:: 1596134

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 9; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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