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Bio-Inspired Nitrile Hydration by Peptidic Ligands Based on L-Cysteine, L-Methionine or L-Penicillamine and Pyridine-2,6-dicarboxylic Acid

School of Chemistry F11, The University of Sydney, Sydney, NSW 2006, Australia
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These authors contributed equally to this work.
Molecules 2014, 19(12), 20751-20767; https://doi.org/10.3390/molecules191220751
Received: 2 September 2014 / Revised: 6 November 2014 / Accepted: 16 November 2014 / Published: 12 December 2014
(This article belongs to the Special Issue Peptide Chemistry)
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. View Full-Text
Keywords: nitrile hydratase; peptidomimetics; metalloenzyme; amino acid nitrile hydratase; peptidomimetics; metalloenzyme; amino acid
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Byrne, C.; Houlihan, K.M.; Devi, P.; Jensen, P.; Rutledge, P.J. Bio-Inspired Nitrile Hydration by Peptidic Ligands Based on L-Cysteine, L-Methionine or L-Penicillamine and Pyridine-2,6-dicarboxylic Acid. Molecules 2014, 19, 20751-20767.

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