Department of Molecular & Cellular Biochemistry and the Center for Structural Biology, University of Kentucky, Lexington, KY, 40536, USA.
Department of Chemistry & Biochemistry, Ohio State University, Columbus, OH, 43210, USA.
Sci Rep. 2019 Dec 30;9(1):20267. doi: 10.1038/s41598-019-56722-2.
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.
结核分枝杆菌是世界上最致命的传染病的病原体。目前正在努力针对蛋氨酸生物合成途径进行靶向治疗，因为该途径不在宿主代谢范围内。同型丝氨酸转乙酰酶 MetX 在该途径的关键步骤中将 L-同型丝氨酸转化为 O-乙酰-L-同型丝氨酸。为了便于基于结构的药物设计，我们确定了三种 MetX 蛋白的高分辨率晶体结构，包括结核分枝杆菌（MtMetX）、脓肿分枝杆菌（MaMetX）和偶发分枝杆菌（MhMetX）。对来自其他细菌和真菌物种的同型丝氨酸转乙酰酶的比较表明，这些酶之间具有高度的结构保守性。利用结合了辅因子的同源结构，我们分析了 MetX 的潜在配体结合能力。围绕催化丝氨酸的深活性位点隧道在映射过程中产生了许多共识簇，表明 MtMetX 具有很高的成药性。
