title: Origin of the Regioselective Fatty-Acid Hydroxylation versus Decarboxylation by a Cytochrome P450 Peroxygenase: What Drives the Reaction to Biofuel Production?
abstract: The cytochromes P450 are heme-based mono-oxygenases or peroxygenases involved in vital reaction processes for human health. A recently described P450 per-oxygenase, OleTJE , converts long-chain fatty acids to terminal olefins and as such may have biotechnological relevance in biodiesel production. However, the reaction produces significant amounts of α- and β-hydroxylation by-products, and their origin are poorly understood. Herein, we elucidate through a QM/MM study on the bifurcation pathways how the three possible products are generated and show how the enzyme can be further engineered for optimum desaturase activity. The studies showed that the polarity and the solvent accessibility of the substrate in the binding pocket destabilize the OH-rebound pathways and kinetically enable a thermodynamically otherwise unfavorable decarboxylation reaction. The origins of the bifurcation pathways are analyzed with valence-bond models that highlight the differences in reaction mechanism.
authors.affiliation: Manchester Institute of Biotechnology and, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Abayomi S
authors.identifier: http://orcid.org/0000-0002-6989-0342
authors.initials: AS
authors.lastname: Faponle
authors.affiliation: Manchester Institute of Biotechnology and, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Matthew G
authors.identifier: http://orcid.org/0000-0001-5130-1266
authors.initials: MG
authors.lastname: Quesne
authors.affiliation: Manchester Institute of Biotechnology and, School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK. sam.devisser@manchester.ac.uk.
authors.forename: Sam P
authors.identifier: http://orcid.org/0000-0002-2620-8788
authors.initials: SP
authors.lastname: de Visser
mesh_terms: D056804:Biofuels; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D003653:Decarboxylation; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D056804:Biofuels; D005227:Fatty Acids; D003577:Cytochrome P-450 Enzyme System; D010544:Peroxidases; C066418:cytochrome P-450 peroxygenase
keywords: bioengineering; cytochromes; density functional calculations; heme proteins; iron