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Open Chen Wang Phd Dissertation The Pennsylvania State University The Graduate School Department of Biochemistry and Molecular Biology MECHANISTIC STUDIES ON THREE ORGANOPHOSPHONATE-PROCESSING ENZYMES, HppE, HEPD AND MPnS A Dissertation in Biochemistry by Chen Wang 2015 Chen Wang Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy May 2015 The dissertation of Chen Wang was reviewed and approved* by the following: Joseph Martin Bollinger, Jr. Professor of Chemistry Professor of Biochemistry and Molecular Biology Dissertation Co-Advisor Co-Chair of Committee Carsten Krebs Professor of Chemistry Professor of Biochemistry and Molecular Biology Dissertation Co-Advisor Co-Chair of Committee Squire J. Booker Professor of Chemistry Professor of Biochemistry and Molecular Biology Michael T. Green Associate Professor of Chemistry James H. Tumlinson Ralph O. Mumma Professor of Entomology Director, Center for Chemical Ecology Scott B. Selleck Professor and Head, Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School ii ABSTRACT Naturally occurring phosphonates and phosphinates have bioactivities (e.g., herbicidal, antibiotic) that are useful in agriculture and medicine. Phosphonate and phosphinate compounds can potently inhibit enzymes in various metabolic pathways by functioning as stable mimics of phosphate esters and carboxylic acids. Biosynthetic pathways to phosphonate and phosphinate compounds have proven to be treasure troves for the discovery of unusual enzymatic reactions. The investigation of these conserved pathways has revealed three unprecedented biochemical steps catalyzed by the non-heme-iron(II) enzymes, HppE [(S)-2-hydroxypropyl-1-phosphonate epoxidase], HEPD (2-hydroxyethylphosphonate dioxygenase) and MPnS (methylphosphonate synthase). The work described herein focused on understanding both the mechanisms of the individual reactions and the structural/functional features of each enzyme important in specifying its reaction and pathway. The iron-dependent epoxidase, HppE, converts (S)-2-hydroxypropyl-1-phosphonate (S- HPP) to the antibiotic, fosfomycin [(1R, 2S)-epoxypropylphosphonate], in an unusual 1,3- dehydrogenation of a secondary alcohol to an epoxide. HppE had been classified as an oxidase, with proposed mechanisms differing primarily in the identity of the O2-derived iron complex that abstracts hydrogen (H•) from C1 of S-HPP to initiate epoxide ring closure. In my work, we showed that the preferred co-substrate is actually H2O2 and that HppE therefore almost certainly employs an iron(IV)-oxo complex as the H• abstractor. Reaction with H2O2 is accelerated by bound substrate and produces fosfomycin catalytically with a stoichiometry of unity. The ability of catalase to suppress the HppE activity previously attributed to its direct utilization of O2 showed that reduction of O2 and utilization of the resultant H2O2 were actually operant. The mechanism of the conversion of 2-hydroxyethylphosphonate to hydroxymethylphosphonate (2-HEP) catalyzed by iron-dependent enzyme, HEPD during the iii biosynthesis of the commercial herbicide, phosphinothricin, had been enigmatic. By using rapid- kinetic and spectroscopic methods, we detected an iron(IV)-oxo (ferryl) intermediate in the HEPD reaction. Kinetic analysis suggested that the intermediate is kinetically competent to be on the productive pathway. The accumulation of this intermediate only with substrate having deuterium in the abstracted pro-S position of C2 of 2-HEP implied that the ferryl intermediate 2 abstracts this hydrogen, but the increased accumulation of the ferryl complex in H2O solvent implied that the hydrogen becomes solvent-exchangeable before the ferryl abstracts it. To account for these unanticipated results, a mechanism involving initial abstraction of the pro-S hydrogen by an Fe(III)-superoxo precursor to the ferryl complex, transfer of a hydroxyl group containing the originally abstracted hydrogen to C2 concomitant with formation of the ferryl complex, and an unprecedented abstraction of H• from the newly installed C2 OH group by the ferryl complex was proposed. Like HEPD, the iron-dependent oxygenase, MPnS, also catalyzes the 4e--oxidative C-C cleavage of 2-HEP, but generates different products, methylphosphonate and CO2. MPnS, HEPD, and HppE have quite striking structural similarity and utilize identical or similar phosphonate substrates, but they employ different oxidants, O2 or H2O2, to effect three completely different - reactions. By using H2O2, HppE effects a 2e oxidation (epoxide installing 1,3-dehydrogenation) of S-HPP. HEPD and MPnS catalyze distinct 4e--oxidative C1-C2-cleaving transformations of 2- HEP, in each case with O2 as the oxidant. We explored the distinct but potentially overlapping catalytic capabilities of the three enzymes on the two different phosphonate substrates with the two different oxidants. As expected from its reassignment as a peroxidase, HppE fails to catalyze - a 4e -oxidative C-C cleavage reaction with O2 as oxidant. However, we found that both MPnS - and HEPD can catalyze the 2e dehydrogenation of 2-HEP with H2O2 rather than O2 as the oxidant. HEPD catalyzed only a fraction of a turnover under the conditions examined, consistent iv with the fact that it is an oxygenase. By contrast, MPnS, also a known oxygenase, surprisingly catalyzed up to 25 turnovers of 2-HEP to the corresponding aldehyde with H2O2 as the oxidizing co-substrate. The physiological relevance of this activity is unknown. In sum, all three enzymes possess some peroxidase activity, with HppE being by far the most efficient, but only HEPD and MPnS exhibit the 4e--oxidative C-C-cleavage activity. v Contents List of Figures .......................................................................................................................... viii List of Tables ........................................................................................................................... xii List of Abbreviations ............................................................................................................... xiii List of Schemes ........................................................................................................................ xvi Acknowledgements .................................................................................................................. xvii Chapter 1 Introduction to Phosphonate-Processing Enzymes, HppE, HEPD and MPnS ........ 1 1.1 Phosphonate and phosphinate natural products and their biosynthetic pathways ............ 1 1.1.1 Fosfomycin, a clinically useful antibiotic, and its biosynthesis .............................. 2 1.1.1.1 The antibiotic function of fosfomycin .......................................................... 3 1.1.1.2 The biosynthetic pathways of fosfomycin .................................................... 7 1.1.2 Phosphinothrincin and its biosynthetic pathway ..................................................... 11 1.1.2.1 Phosphinothrincin, an active component of herbicide ................................. 11 1.1.2.2 Biosynthesis of Phosphinothrincin ............................................................... 13 1.1.3 Methylphosphonate and its biosynthetic pathway in Nitrosopumilus maritimus .... 13 1.2 The phosphonate-processing non-heme-iron(II) enzymes, HppE, HEPD and MPnS ....... 15 1.2.1 (S)-2-hydroxypropylphosphonic acid epoxidase (HppE) is a unique epoxidase..... 15 1.2.1.1 HppE is a non-heme-iron(II) dependent epoxidase ...................................... 15 1.2.1.2 HppE is a peroxidase, rather than an oxidase ............................................... 19 1.2.1.3 The discussion on the epoxide ring closure of HppE-catalyzed epoxidation of S-HPP ....................................................................................... 25 1.2.1.4 Other enzyme-catalyzed epoxidation reactions and their catalytic mechanisms ...................................................................................................... 34 Flavin-dependent epoxidase ..................................................................................... 47 Cofactor-independent epoxidases ............................................................................ 49 Epoxide Formation via Intramolecular Nucleophilic Substitution .......................... 49 1.2.2 HEPD catalyzes an unprecedented C-C cleaving reaction ...................................... 52 1.2.2.1 Previous studies established that HEPD was a non-heme-iron dioxygenase ...................................................................................................... 52 1.2.2.2 The proposed catalytic mechanisms of HEPD ............................................. 55 1.2.3 MPnS catalyzes a novel oxidative C-C cleaving reaction of 2-HEP ...................... 59 1.3 The stereospecific C-H activation in HppE, HEPD and MPnS catalysis .......................... 61 1.3.2 The C-H bond activation by FeIII-hydroperoxo intermediate .................................. 68 1.3.3 The C-H bond activation by FeIV-oxo intermediate ........................................ 71 1.4 Outlook .............................................................................................................................. 76 vi 1.4.1 The accumulation and characterization of the postulated substrate-derived carbocation intermediate in the HppE catalyzed reaction with R-1-HPP ................. 76 1.4.2 The amino acid(s) involving in the deprotonation of H2O2 in the HppE catalyzed peroxidation
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