This proposal focuses on the synthesis and reactivity of small-molecule metal complexes as models of NxSy-Mn+ metalloproteins. The metalloenzymes peptide deformylase (PDF) and superoxide reductase (SOR) share common structural elements. They both contain a mononuclear iron center coordinated by an uncommon cysteinate thiolate and two or four histidine ligands. The PDF class of enzymes are important targets for antibacterial, antimalarial, and anticancer therapies. Most bacterial PDFs employ an iron(ll) center bound by His2Cys ligands and catalyze the hydrolytic cleavage of the N-terminal formyl group of nascent polypeptides. Substitution of Zn(ll) for Fe(ll) renders PDF inactive in most cases, even though Zn(ll) is normally Nature's preferred choice for catalyzing hydrolysis reactions. However, the zinc(ll) ion is active in eukaryotic PDFs, as well as in one type of bacterial PDF. These observations lead to the following questions: Why does the enzyme utilize a redox-active iron(ll) ion to perform a non-redox role? What causes the variation in activity for Zn""""""""? What is the influence of the uncommon thiolate donor? What is the mechanism? The enzyme SOR contains a unique iron(ll) active site with one Cys and four His ligands, and catalyzes the reduction of O2"""""""" to H2O2. The fundamental chemistry of superoxide has been implicated in a number of diseases. Questions regarding SOR include: What is the nature of the O2"""""""" binding site? What intermediates are formed during reduction of O2~ by Fe""""""""? What factors (e.g. redox potential, spin state, donor set) control O2~ reduction? What factors are critical for the release of H2O2? Principles of ligand design and coordination chemistry will be used to synthesize model complexes of PDF and SOR. The PDF models will be examined for their hydrolytic reactivity. The SOR models will be studied in reactions with O2~ and related oxygenic species. Both types of complexes will be interrogated in order to determine broad patterns of reactivity, mechanism, and structure/function relationships in N/S-ligated metal centers. Knowledge regarding the synthesis and reactivity of new NxSy ligands and there metal complexes will be advanced. Relevance: The information obtained from this work will be potentially useful for the design of new antibiotics, as well as the treatment of a wide variety of diseases in which reactive oxygen species are implicated (e.g. Parkinson's, Alzheimer's, cancer). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM062309-06A2
Application #
7317911
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Fabian, Miles
Project Start
2001-04-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
6
Fiscal Year
2007
Total Cost
$296,828
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Sahu, Sumit; Zhang, Bo; Pollock, Christopher J et al. (2016) Aromatic C-F Hydroxylation by Nonheme Iron(IV)-Oxo Complexes: Structural, Spectroscopic, and Mechanistic Investigations. J Am Chem Soc 138:12791-12802
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Sahu, Sumit; Widger, Leland R; Quesne, Matthew G et al. (2013) Secondary coordination sphere influence on the reactivity of nonheme iron(II) complexes: an experimental and DFT approach. J Am Chem Soc 135:10590-3
Widger, Leland R; Siegler, Maxime A; Goldberg, David P (2013) Sulfide Oxidation by O2: Synthesis, Structure and Reactivity of Novel Sulfide-Incorporated Fe(II) Bis(imino)pyridine Complexes. Polyhedron 58:179-189
Widger, Leland R; Jiang, Yunbo; Siegler, Maxime A et al. (2013) Synthesis and ligand non-innocence of thiolate-ligated (N4S) Iron(II) and nickel(II) bis(imino)pyridine complexes. Inorg Chem 52:10467-80
McQuilken, Alison C; Ha, Yang; Sutherlin, Kyle D et al. (2013) Preparation of non-heme {FeNO}7 models of cysteine dioxygenase: sulfur versus nitrogen ligation and photorelease of nitric oxide. J Am Chem Soc 135:14024-7

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