title: Artificial Metalloenzymes with the Neocarzinostatin Scaffold: Toward a Biocatalyst for the Diels-Alder Reaction.
abstract: A copper(II) cofactor coupled to a testosterone anchor, copper(II)-(5-(Piperazin-1-yl)-1,10-phenanthroline)testosterone-17-hemisuccinamide (10) was synthesized and associated with a neocarzinostatin variant, NCS-3.24 (KD =3 μm), thus generating a new artificial metalloenzyme by following a "Trojan horse" strategy. Interestingly, the artificial enzyme was able to efficiently catalyze the Diels-Alder cyclization reaction of cyclopentadiene (1) with 2-azachalcone (2). In comparison with what was observed with cofactor 10 alone, the artificial enzymes favored formation of the exo products (endo/exo ratios of 84:16 and 62:38, respectively, after 12 h). Molecular modeling studies assigned the synergy between the copper complex and the testosterone (KD =13 μm) moieties in the binding of 10 to good van der Waals complementarity. Moreover, by pushing the modeling exercise to its limits, we hypothesize on the molecular grounds that are responsible for the observed selectivity.
authors.affiliation: Institute de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, CNRS, Université Paris-Sud, Bât. 420, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France.
authors.forename: Wadih
authors.initials: W
authors.lastname: Ghattas
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, Edifici C.n., 08193, Cerdonyola del Vallès, Barcelona, Spain.
authors.forename: Lur
authors.initials: L
authors.lastname: Cotchico-Alonso
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, Edifici C.n., 08193, Cerdonyola del Vallès, Barcelona, Spain.
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), UMR 9198, CEA, CNRS, Université Paris-Sud, Bât. 430, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Urvoas
authors.affiliation: Institute de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, CNRS, Université Paris-Sud, Bât. 420, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France.
authors.forename: Maëva
authors.initials: M
authors.lastname: Rousseau
authors.affiliation: Institute de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, CNRS, Université Paris-Sud, Bât. 420, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France. jean-pierre.mahy@u-psud.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mahy
authors.affiliation: Institute de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182, CNRS, Université Paris-Sud, Bât. 420, rue du Doyen Georges Poitou, 91405, Orsay Cedex, France. remy.ricoux@u-psud.fr.
authors.forename: Rémy
authors.initials: R
authors.lastname: Ricoux
mesh_terms: D055162:Biocatalysis; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D061565:Cycloaddition Reaction; D004798:Enzymes / Q000378:metabolism*; D008667:Metalloproteins / Q000378:metabolism*; D062105:Molecular Docking Simulation; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D009353:Zinostatin / Q000378:metabolism*
chemical_list: D004798:Enzymes; D008667:Metalloproteins; D009353:Zinostatin
keywords: artificial metalloenzymes; biocatalysis; copper complexes; diels-alder cyclization reaction; molecular modeling