2025-07-03 バース大学
<関連情報>
- https://www.bath.ac.uk/announcements/research-opens-up-new-avenue-for-tuberculosis-drug-discovery/
- https://www.jbc.org/article/S0021-9258(25)02152-0/fulltext
結核菌由来α-メチルアシル-CoAラセマーゼによるアシル-CoAエステル認識の分子基盤 Molecular basis of acyl-CoA ester recognition by α-methylacyl-CoA racemase from Mycobacterium tuberculosis
Otsile O. Mojanaga ∙ Timothy J. Woodman ∙ Matthew D. Lloyd ∙ K. Ravi Acharya
The Journal of Biological Chemistry Published:May 28, 2025
DOI:https://doi.org/10.1016/j.jbc.2025.110302
Abstract
α-Methylacyl-CoA racemase (AMACR; P504S) enzyme plays a vital role in branched-chain fatty acid metabolism by catalyzing the conversion of 2-methyl-branched fatty acyl-CoAs into a near 1 to 1 mixture of the (2R)- and (2S)-epimers, enabling further metabolism. α-Methylacyl-CoA racemase from Mycobacterium tuberculosis (MCR) has been explored as a model to understand the AMACR racemization mechanism and as a drug target. Here we present a detailed analysis of a new MCR wild-type crystal structure to provide insights into the MCR racemization mechanism and the molecular features that contribute enzyme activity and selectivity. Specifically, we report a structure of wild-type MCR (in tetragonal space group I422, a new crystal form) along with 12 structures of MCR in complex with branched-chain 2-methylacyl-CoA esters (ibuprofenoyl-CoA, ±-fenoprofenoyl-CoA, S-ketoprofenoyl-CoA, ±-flurbiprofenoyl-CoA, S-naproxenoyl-CoA, S-2-methyldecanoyl-CoA, and isobutanoyl-CoA) and straight-chain acyl-CoA esters (decanoyl-CoA, octanoyl-CoA, hexanoyl-CoA, butanoyl-CoA, acetyl-CoA) in the range of 1.88 to 2.40 Å resolution. These detailed molecular structures enhance our understanding of substrate recognition and, coupled with extensive enzyme inhibition assays, provide a framework for the rational structure-based drug design of selective and potent MCR inhibitors to combat M. tuberculosis in the future.
