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.
Highlights
Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease
MetX can be divided into two distinct structural domains, the catalytic domain, and the lid domain
All three MetX structures show a high degree of overall similarity to previously studied homoserine transacetylase (HTA) from both bacteria and fungi
Summary
Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. The three solved MetX structures include residues 15–70, 77–372 from MhMetX (Fig. 2A), 10–379 from MaMetX (Fig. 2B), and 7–372 from MtMetX (Fig. 2C). Thr61/61/64, Arg227/227/230, Tyr234/234/237, and Asp351/351/358 for MhMetX, MtMetX, and MaMetX respectively all surround the active site to help facilitate the binding of acetyl-CoA and homoserine (Fig. 3B)[20].
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