9I33 | pdb_00009i33

Molecular basis of acyl-CoA ester recognition by alpha-methylacyl-CoA racemase from Mycobacterium tuberculosis.

(2025) J Biological Chem : 110302-110302

• PubMed: 40447188 Search on PubMed
• DOI: https://doi.org/10.1016/j.jbc.2025.110302
• Primary Citation of Related Structures:  
  9I2T, 9I2U, 9I2V, 9I2W, 9I2X, 9I2Z, 9I30, 9I31, 9I32, 9I33, 9I34, 9I35, 9I36


• PubMed Abstract: 
  

  α-Methylacyl-CoA racemase (AMACR; P504S) enzyme plays a vital role in branched-chain fatty acid metabolism by catalysing 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 ? 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 Mycobacterium tuberculosis in the future.

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Organizational Affiliation: 

Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.