Mononuclear Non-Heme Iron(II) Models of Metalloenzymes with Mixed N/S Donors: Small Molecule Activation

Enzyme models;Mechanisms;Chemistry

McQuilken, Alison CarolGoldberg, David P. ;

Johns Hopkins University

关键词: Enzyme models;    Mechanisms;    Chemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/40200/MCQUILKEN-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

This thesis presents the progress made in constructing synthetic and functional models of a small subset of iron oxygenases, which are enzymes responsible for the activation of dioxygen (O2) for a myriad of biological functions. The subset of interest is comprised of metalloenzymes containing a mononuclear, non-heme iron(II) center that incorporates sulfur donors in the first coordination sphere, as described in Chapter 1. In particular, the synthetic iron(II) complexes of interest are bound by polydentate N4S(thiolate) ligands to mimic the coordination sphere found in the active sites of cysteine dioxygenase (CDO) and superoxide reductase (SOR). In SOR, the cysteine (Cys) thiolate ligation plays an important role in tuning the electronic properties of the iron(II) center to aid in the detoxification of superoxide (O2−) to give the one-electron-reduced hydrogen peroxide (H2O2). In CDO, the Cys substrate undergoes sulfur oxygenation by O2 to give Cys-sulfinic acid to control levels of cysteine in biological systems. Synthetic models are used to aid in the understanding of many aspects of the structure and mechanism of metalloenzymes. Nitric oxide (NO) is another important molecule found in biological systems and is also used in synthetic molecules to probe O2 binding sites and mechanisms. The reactivity of O2 with iron-thiolate complexes is difficult to control, due to the many oxidation pathways that generate Fe- and S-oxidized products. Chapter 2 will discuss the synthesis of a new structural and functional model for the active site of cysteine dioxygenase, [FeII(N3PyS)(CH3CN)]BF4, utilizing the pentadentate 4N/1S(thiolate) ligand N3PySH. The reaction of this model complex with O2 resulted in a rare example of sulfur oxygenation of a synthetic iron(II)-thiolate complex, affording the doubly oxygenated sulfinate product [FeII(N3PySO2)(NCS)], which was crystallographically characterized. The influence of the thiolate donor on the redox potential and O2 reactivity of this FeII complex is also examined.Nitric oxide was used to probe the O2 binding site of the CDO model complex [FeII(N3PyS)(CH3CN)]+ in Chapter 3. The synthesis and spectroscopic characterization of the resulting iron nitrosyl, [Fe(NO)(N3PyS)]+, result in the first structural and electronic model of NO-bound cysteine dioxygenase. The nearly isostructural all-N-donor analog [Fe(NO)(N4Py)]2+ was also prepared. Comparison of these two synthetic iron nitrosyl complexes provides insight regarding the influence of S vs N ligation in {FeNO}7 species. One key difference occurs upon photoirradiation, which causes the fully reversible release of NO from the thiolate-ligated [Fe(NO)(N3PyS)]+, but not from [Fe(NO)(N4Py)]2+.In chapter 4, the O2 reactivity of the iron nitrosyl [Fe(NO)(N3PyS)]+ will be discussed. This {FeNO}7 complex is oxidized to [FeIII(NO2)(N3PyS)]+ by O2 in acetonitrile. The rate of this oxidation reaction is greatly increased when performed under photoirradiation conditions, implicating NO dissociation from the iron center as the first step. Aerobic irradiation in different solvents, as well as trapping experiments with thiophenol support a mechanism whereby the photogenerated 5-coordinate [FeII(N3PyS)] complex could be oxidized to an FeIII-superoxo intermediate. Rebound by NO would give an FeIII-peroxynitrite intermediate which then decays to give [FeIII(NO2)(N3PyS)]+. This FeIII-NO2 complex also undergoes oxygen atom transfer to PPh3, affording OPPh3 and the starting {FeNO}7 complex.