title: Theoretical calculations of the catalytic triad in short-chain alcohol dehydrogenases/reductases.
abstract: Three highly conserved active site residues (Ser, Tyr, and Lys) of the family of short-chain alcohol dehydrogenases/reductases (SDRs) were demonstrated to be essential for catalytic activity and have been denoted the catalytic triad of SDRs. In this study computational methods were adopted to study the ionization properties of these amino acids in SDRs from Drosophila melanogaster and Drosophila lebanonensis. Three enzyme models, with different ionization scenarios of the catalytic triad that might be possible when inhibitors bind to the enzyme cofactor complex, were constructed. The binding of the two alcohol competitive inhibitors were studied using automatic docking by the Internal Coordinate Mechanics program, molecular dynamic (MD) simulations with the AMBER program package, calculation of the free energy of ligand binding by the linear interaction energy method, and the hydropathic interactions force field. The calculations indicated that deprotonated Tyr acts as a strong base in the binary enzyme-NAD(+) complex. Molecular dynamic simulations for 5 ns confirmed that deprotonated Tyr is essential for anchoring and orientating the inhibitors at the active site, which might be a general trend for the family of SDRs. The findings here have implications for the development of therapeutically important SDR inhibitors.
authors.affiliation: Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway.
authors.forename: Osman A B S M
authors.initials: OA
authors.lastname: Gani
authors.forename: Olayiwola A
authors.initials: OA
authors.lastname: Adekoya
authors.forename: Laura
authors.initials: L
authors.lastname: Giurato
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.forename: Jan-Olof
authors.initials: JO
authors.lastname: Winberg
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
mesh_terms: D000426:Alcohol Dehydrogenase / Q000737:chemistry* / Q000648:ultrastructure*; D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D002384:Catalysis; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase