title: Direct hydroxide attack is a plausible mechanism for amidase antibody 43C9.
abstract: Direct hydroxide attack on the scissile carbonyl of the substrate has been suggested as a likely mechanism for esterase antibodies elicited by phosphonate haptens, which mimic the transition states for the alkaline hydrolysis of esters.1 The unique amidase activity of esterase antibody 43C9 has been attributed to nucleophilic attack by an active-site histidine residue.2 Yet, the active site of 43C9 is strikingly similar to those of other esterase antibodies, particularly 17E8. We have carried out quantum mechanical calculations, molecular dynamics simulations, and free energy calculations to assess the mechanism involving direct hydroxide attack for 43C9. Results support this mechanism and suggest that the mechanism is plausible for other antiphosphonate antibodies that catalyze the hydrolysis of (p-nitro)phenyl esters.
authors.affiliation: Graduate Group in Biophysics and Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94143-2240, USA. ltchong@stanford.edu
authors.forename: Lillian T
authors.initials: LT
authors.lastname: Chong
authors.forename: Pradipta
authors.initials: P
authors.lastname: Bandyopadhyay
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kollman
mesh_terms: D000581:Amidohydrolases / Q000276:immunology* / Q000378:metabolism; D017151:Antibodies, Catalytic / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006868:Hydrolysis; D017665:Hydroxyl Radical / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D017151:Antibodies, Catalytic; D017665:Hydroxyl Radical; D006639:Histidine; D000581:Amidohydrolases; C019665:amidase