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 journalArticlepeer-review

10 Scopus citations

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 languageEnglish
Article number20267
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

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

ASJC Scopus subject areas

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