Structural Dynamics of the Methyl-Coenzyme M Reductase Active Site Are Influenced by Coenzyme F430 Modifications

• DOI: 10.1021/acs.biochem.4c00168
• Publication Date: 2024-06-25T03:19:13Z
• Authors: Marcelo D. Polêto; Kylie D. Allen; Justin A. Lemkul
• Keywords: Thioether; Coenzyme A

Methyl-coenzyme M reductase (MCR) is a central player in methane biogeochemistry, governing methanogenesis and the anaerobic oxidation of (AOM) methanogens methanotrophs (ANME), respectively. The prosthetic group MCR coenzyme F430, nickel-containing tetrahydrocorphin. Several modified versions F430 have been discovered, including 172-methylthio-F430 (mtF430) used by ANME-1 MCR. Here, we employ molecular dynamics (MD) simulations to investigate active site from Methanosarcina acetivorans when bound canonical compared 172-thioether variants substrates (methyl-coenzyme B) for formation. Our highlight importance Gln Val substitution accommodating 172 methylthio modification Modifications at position disrupt substrate positioning M. However, some replicates, reorganization maintain suggests that could be accommodated methanogenic We additionally report first quantitative estimate intrinsic electric fields are pivotal driving results suggest field aligned along CH3-S-CoM thioether bond facilitates homolytic cleavage, coinciding with proposed catalytic mechanism. Structural perturbations, however, weaken misalign these fields, emphasizing structure maintaining their integrity. In conclusion, our deepen understanding dynamics, enzyme's organizational role catalysis, interplay between electrostatics.