title: Catalytic roles of active-site residues in 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase: an ONIOM/DFT study.
abstract: The catalytic mechanism of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (MHPCO) has been systematically studied using DFT and ONIOM(DFT:MM) methods. MHPCO catalyzes the hydroxylation and subsequent ring-opening of the aromatic substrate MHPC to give the aliphatic product α-(N-acetylaminomethylene)succinic acid (AAMS). Our calculations show that the active-site residues Arg211 and Tyr223 have a minor effect on the reaction, while the peptide bond of Pro295-Ala296, the side chain of Tyr82 and several crystal water molecules affect the reaction energy profile considerably. Both DFT and ONIOM calculations show that the ring-opening pathway B, in which an epoxy transition state is formed, is more favored than the direct C2-C3 cleavage pathway A. Different QM/MM partitioning schemes have been used to study the enzymatic reaction, and the results show that both the reaction barriers for the hydroxylation and the ring-opening pathways are sensitive to the QM/MM partitioning.
authors.affiliation: School of Chemistry, National University of Ireland-Galway, Galway, Ireland.
authors.forename: Boxue
authors.initials: B
authors.lastname: Tian
authors.forename: Åke
authors.initials: Å
authors.lastname: Strid
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
mesh_terms: D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D006900:Hydroxylation; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000378:metabolism; D009539:Nicotinic Acids / Q000737:chemistry / Q000378:metabolism; D011789:Quantum Theory
chemical_list: C106693:2-methyl-3-hydroxypyridine-5-carboxylic acid; D009539:Nicotinic Acids; D006899:Mixed Function Oxygenases; C019483:methylhydroxypyridine-carboxylate dioxygenase