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

Mycobacterium tuberculosis is cause of the world9s 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 MetA 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 MetA proteins, including M. tuberculosis (MtMetA), Mycolicibacterium abscessus (MaMetA), and Mycolicibacterium hassiacum (MhMetA). Comparison to other homoserine transacetylase family-members reveals a high degree of structural conservation. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetA. The deep active-site tunnel surrounding the catalytic serine yielded a number of consensus clusters during mapping, suggesting that MtMetA is highly druggable.