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      Diiron monooxygenases in natural product biosynthesis

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          Abstract

          Two new families of diiron cluster-containing oxygenases serve as tailoring enzymes for NRPS and PKS biosynthetic systems.

          Abstract

          Covering: up to 2017

          The participation of non-heme dinuclear iron cluster-containing monooxygenases in natural product biosynthetic pathways has been recognized only recently. At present, two families have been discovered. The archetypal member of the first family, CmlA, catalyzes β-hydroxylation of l- p-aminophenylalanine ( l-PAPA) covalently linked to the nonribosomal peptide synthetase (NRPS) CmlP, thereby effecting the first step in the biosynthesis of chloramphenicol by Streptomyces venezuelae. CmlA houses the diiron cluster in a metallo-β-lactamase protein fold instead of the 4-helix bundle fold of nearly every other diiron monooxygenase. CmlA couples O 2 activation and substrate hydroxylation via a structural change caused by formation of the l-PAPA-loaded CmlP:CmlA complex. The other new diiron family is typified by two enzymes, AurF and CmlI, which catalyze conversion of aryl-amine substrates to aryl-nitro products with incorporation of oxygen from O 2. AurF from Streptomyces thioluteus catalyzes the formation of p-nitrobenzoate from p-aminobenzoate as a precursor to the biostatic compound aureothin, whereas CmlI from S. venezuelae catalyzes the ultimate aryl-amine to aryl-nitro step in chloramphenicol biosynthesis. Both enzymes stabilize a novel type of peroxo-intermediate as the reactive species. The rare 6-electron N-oxygenation reactions of CmlI and AurF involve two progressively oxidized pathway intermediates. The enzymes optimize efficiency by utilizing one of the reaction pathway intermediates as an in situ reductant for the diiron cluster, while simultaneously generating the next pathway intermediate. For CmlI, this reduction allows mid-pathway regeneration of the peroxo intermediate required to complete the biosynthesis. CmlI ensures specificity by carrying out the multistep aryl-amine oxygenation without dissociating intermediate products.

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          Most cited references72

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          Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms.

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            Dioxygen Activation by Enzymes Containing Binuclear Non-Heme Iron Clusters.

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              Crystal structure of a bacterial non-haem iron hydroxylase that catalyses the biological oxidation of methane.

              The 2.2 A crystal structure of the 251K alpha 2 beta 2 gamma 2 dimeric hydroxylase protein of methane monooxygenase from Methylococcus capsulatus (Bath) reveals the geometry of the catalytic di-iron core. The two iron atoms are bridged by exogenous hydroxide and acetate ligands and further coordinated by four glutamate residues, two histidine residues and a water molecule. The dinuclear iron centre lies in a hydrophobic active-site cavity for binding methane. An extended canyon runs between alpha beta pairs, which have many long alpha-helices, for possible docking of the reductase and coupling proteins required for catalysis.
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                Author and article information

                Journal
                NPRRDF
                Natural Product Reports
                Nat. Prod. Rep.
                Royal Society of Chemistry (RSC)
                0265-0568
                1460-4752
                2018
                2018
                : 35
                : 7
                : 646-659
                Affiliations
                [1 ]Department of Chemistry
                [2 ]University of Minnesota
                [3 ]Minneapolis
                [4 ]USA
                [5 ]Department of Biochemistry, Molecular Biology and Biophysics
                Article
                10.1039/C7NP00061H
                6051903
                29552683
                1657b9f0-fe5a-40e5-8899-762724fd9f9a
                © 2018

                http://rsc.li/journals-terms-of-use

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