Abstract

A large class of metalloproteins utilize a mixed nitrogen/sulfur coordination environment to hold the metal ion (Fe, Ni, Co, Cu, Zn) in the active site, including blue copper proteins, nitrile hydratase, alcohol dehydrogenase, and peptide deformylase (PDF). The long term objective of the proposed research is the development of the coordination chemistry of new nitrogen/sulfur metal complexes as it relates to the structure and functioning of certain of these metalloproteins. In particular, the theme of this proposal concerns the synthesis and reactivity of a new family of mixed nitrogen/sulfur metal complexes that are designed to be structural and functional models of peptide deformylase. Peptide deformylase (PDF) is a bacterial metallohydrolase enzyme with a tetrahedral Fe(II) center. It is currently under scrutiny as an attractive target for new antibiotic drugs. Study of the new class of L(N,S)-M (M = Fe, Ni, Co, Zn) complexes designed here should shed light on important structure/function relationships concerning PDF and other related metallohydrolases. These compounds should also exhibit new properties and reactivity that will provide valuable information in the study of other N,S-metal sites in biology such as nitrile hydratase, alcohol dehydrogenase, or mutant forms of carbonic anhydrase. Objectives of the propose research include the synthesis of ligands designed to mimic the 2 His, 1 Cys ligation found in PDF. New organic syntheses will be developed to prepare three-coordinate, tripodal dipyridyl- and diimidazolyl-alkylthiolate ligands. Complexes of the type [L(M(II)X] (L = N2Sthiolate; M = Fe, Ni, Co, Zn; X = halogen, monoanion, solvent, etc.] should be accessible. The hydrolytic capabilities of these complexes toward amide, and ester substrates will be determined. Mechanistic investigations (e.g. isolation of intermediates, kinetic studies) will be undertaken. Spectroscopic analysis (NMR, EPR, UV-vis, electrochemistry) will be used to characterize ground state complexes as well intermediates along the reaction path. The isolation and characterization of [LM(II)OH] complexes will be emphasized, given their presumed role as the active nucleophilic agent during hydrolytic cleavage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062309-04
Application #
6732740
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Preusch, Peter C
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$178,027
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

McQuilken, Alison C; Matsumura, Hirotoshi; Dürr, Maximilian et al. (2016) Photoinitiated Reactivity of a Thiolate-Ligated, Spin-Crossover Nonheme {FeNO}(7) Complex with Dioxygen. J Am Chem Soc 138:3107-17
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
Besold, Angelique N; Widger, Leland R; Namuswe, Frances et al. (2016) Revisiting and re-engineering the classical zinc finger peptide: consensus peptide-1 (CP-1). Mol Biosyst 12:1183-93
Sahu, Sumit; Quesne, Matthew G; Davies, Casey G et al. (2014) Direct observation of a nonheme iron(IV)-oxo complex that mediates aromatic C-F hydroxylation. J Am Chem Soc 136:13542-5
Widger, Leland R; Jiang, Yunbo; McQuilken, Alison C et al. (2014) Thioether-ligated iron(II) and iron(III)-hydroperoxo/alkylperoxo complexes with an H-bond donor in the second coordination sphere. Dalton Trans 43:7522-32
Widger, Leland R; Davies, Casey G; Yang, Tzuhsiung et al. (2014) Dramatically accelerated selective oxygen-atom transfer by a nonheme iron(IV)-oxo complex: tuning of the first and second coordination spheres. J Am Chem Soc 136:2699-702
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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