title: Lack of enantioselectivity in the SULT1A3-catalyzed sulfoconjugation of normetanephrine enantiomers: an in vitro and computational study.
abstract: (1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M), V(max), and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket.
authors.affiliation: Service de Biomédecine, Lausanne University Hospital, Lausanne, Switzerland. Eric.Grouzmann@chuv.ch
authors.forename: Eric
authors.initials: E
authors.lastname: Grouzmann
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gualtierotti
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gerber-Lemaire
authors.forename: Karim
authors.initials: K
authors.lastname: Abid
authors.forename: Noureddine
authors.initials: N
authors.lastname: Brakch
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
mesh_terms: D015239:Arylsulfotransferase / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009647:Normetanephrine / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D009647:Normetanephrine; D015239:Arylsulfotransferase; C403170:monoamine-sulfating phenol sulfotransferase