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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Metallobiochemistry Study Section (BMT)
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Preusch, Peter C
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Johns Hopkins University
Schools of Arts and Sciences
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