The goal of the proposed research is to investigate the reactivity of manganese and iron complexes as models of heme metalloenzymes that utilize dioxygen. Heme enzymes such as cytochrome P450, peroxidases, catalases, heme oxygenase, nitric oxide synthase and cytochrome C oxidase all rely upon Mn or Fe active sites to perform an impressive range of critical biological functions involving O2 or its derivatives. Although the functions of these enzymes are highly diverse, there are some mechanistic commonalities involving key intermediates that bring these systems together. These key intermediates involve high-valent metal-oxo (M=O) and metal-(hydro)peroxo (M-OO(H)) species. Understanding the reactivity and spectroscopic features of these species is critically important, yet many questions remain about these species in part because of challenges associated with studying what are unstable and often short-lived intermediates. We will address fundamental questions regarding high-valent M=O species and their precursors, M-OO(H), through a synthetic analog approach. We will utilize ligands known as corrolazines (Czs) and corroles (Cors) to carry out this research. These ligands are designed to stabilize high oxidation states (e.g. MVO). They also support lower-valent complexes such as MIII and MIV, which will be used to study O-O cleavage events.
Aims of this proposal are 1) to synthesize novel high-valent (Cz)M(O) and (Cor)M(O) complexes, determine their structural and spectroscopic properties, and examine their reactivity in biologically relevant transformations and 2) to determine the reactivity of (Cz)M and (Cor)M toward O-O cleavage/O2 activation. Synthetic methods, including ligand design and coordination chemistry, will be used to construct new model complexes of interest. We will correlate the structural and electronic properties of the (Cz)M and (Cor)M (M = Mn, Fe) complexes with reactivity in reactions of direct biological relevance (e.g. hydrogen-atom-transfer (HAT), oxygen-atom-transfer (OAT), and electron-transfer (ET) processes). Reactivity and mechanism will be studied through analysis of products and kinetic measurements with a range of HAT substrates containing C-H and O-H bonds, O-atom acceptor substrates, and ET agents. Comparison of our Mn and Fe chemistry should yield insights regarding why Nature chooses Fe or Mn to perform specific functions. Fundamental information regarding the mechanisms of biomimetic HAT, OAT, ET and related reactions will be obtained.

Public Health Relevance

Heme enzymes that utilize O2 and its derivatives are critical to a number of life processes, and implicated in many disease states. The fundamental knowledge to be obtained by the proposed research will contribute to understanding key mechanistic events in these systems and therefore should aid in the design of novel therapeutic and diagnostic agents in the long term.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM101153-04S1
Application #
9273159
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2013-09-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
$117,295
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
21205
Sahu, Sumit; Goldberg, David P (2016) Activation of Dioxygen by Iron and Manganese Complexes: A Heme and Nonheme Perspective. J Am Chem Soc 138:11410-28
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
Yang, Tzuhsiung; Quesne, Matthew G; Neu, Heather M et al. (2016) Singlet versus Triplet Reactivity in an Mn(V)-Oxo Species: Testing Theoretical Predictions Against Experimental Evidence. J Am Chem Soc 138:12375-86
Zaragoza, Jan Paulo T; Siegler, Maxime A; Goldberg, David P (2016) Rhenium(V)-oxo corrolazines: isolating redox-active ligand reactivity. Chem Commun (Camb) 52:167-70
Joslin, Evan E; Zaragoza, Jan Paulo T; Baglia, Regina A et al. (2016) The Influence of Peripheral Substituent Modification on P(V), Mn(III), and Mn(V)(O) Corrolazines: X-ray Crystallography, Electrochemical and Spectroscopic Properties, and HAT and OAT Reactivities. Inorg Chem 55:8646-60
Jung, Jieun; Neu, Heather M; Leeladee, Pannee et al. (2016) Photocatalytic Oxygenation of Substrates by Dioxygen with Protonated Manganese(III) Corrolazine. Inorg Chem 55:3218-28
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
Baglia, Regina A; Krest, Courtney M; Yang, Tzuhsiung et al. (2016) High-Valent Manganese-Oxo Valence Tautomers and the Influence of Lewis/Brönsted Acids on C-H Bond Cleavage. Inorg Chem 55:10800-10809
Neu, Heather M; Baglia, Regina A; Goldberg, David P (2015) A Balancing Act: Stability versus Reactivity of Mn(O) Complexes. Acc Chem Res 48:2754-64
Neu, Heather M; Jung, Jieun; Baglia, Regina A et al. (2015) Light-driven, proton-controlled, catalytic aerobic C-H oxidation mediated by a Mn(III) porphyrinoid complex. J Am Chem Soc 137:4614-7

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