title: Bio-inspired nitrile hydration by peptidic ligands based on L-cysteine, L-methionine or L-penicillamine and pyridine-2,6-dicarboxylic acid.
abstract: Nitrile hydratase (NHase, EC 4.2.1.84) is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III)- and iron(III)-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate). Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L-S-methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III) and iron(III) and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III), converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers.
authors.affiliation: School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia. cilliandbyrne@googlemail.com.
authors.forename: Cillian
authors.initials: C
authors.lastname: Byrne
authors.affiliation: School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia. tynan.kate@gmail.com.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Houlihan
authors.affiliation: School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia. prarthana.devi@sydney.edu.au.
authors.forename: Prarthana
authors.initials: P
authors.lastname: Devi
authors.affiliation: School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia. paul.jensen.email@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Jensen
authors.affiliation: School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia. peter.rutledge@sydney.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rutledge
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis; D000097:Acetonitriles / Q000737:chemistry*; D055162:Biocatalysis; D020134:Catalytic Domain; D003035:Cobalt / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry*; D006836:Hydro-Lyases / Q000737:chemistry; D007501:Iron / Q000737:chemistry; D008715:Methionine / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000737:chemistry*; D010848:Picolinic Acids / Q000737:chemistry*
chemical_list: D000081:Acetamides; D000097:Acetonitriles; D010848:Picolinic Acids; D003035:Cobalt; C030686:acetamide; D008715:Methionine; D007501:Iron; D006836:Hydro-Lyases; C048831:nitrile hydratase; D010396:Penicillamine; D003545:Cysteine; C004860:dipicolinic acid; C032159:acetonitrile