title: Full reaction mechanism of nitrile hydratase: a cyclic intermediate and an unexpected disulfide switch.
abstract: The full reaction mechanism of nitrile hydratase has remained elusive, despite extensive theoretical and experimental studies. A novel reaction mechanism for nitrile hydratase is proposed here, with remarkable features and very feasible barriers. Our results, obtained on the basis of large quantum-mechanical active site models, identify Cys-SO(-) as the nucleophile, performing a direct nucleophilic attack on the metal-coordinated nitrile. This implies the formation of an intriguing cyclic intermediate, which subsequently is cleaved through attack of the axial cysteine on the sulfenate, thereby forming a disulfide bond. In this mechanism, nitrile hydration occurs without directly involving a water molecule. Subsequent water-mediated disulfide cleavage regenerates the active site. This is the first example of a disulfide switch directly implicated in an enzymatic reaction mechanism.
authors.affiliation: Centre for Theoretical and Computational Chemistry, Department of Chemistry, University of Tromsø , N-9037 Tromsø, Norway.
authors.forename: Kathrin H
authors.initials: KH
authors.lastname: Hopmann
mesh_terms: D003500:Cyclization; D004220:Disulfides / Q000737:chemistry*; D006836:Hydro-Lyases / Q000737:chemistry*
chemical_list: D004220:Disulfides; D006836:Hydro-Lyases; C048831:nitrile hydratase