Synthetic Modeling Chemistry of Iron–Sulfur Clusters in Nitric Oxide Signaling

Nitric oxide (NO) is an important signaling molecule that is involved in many physiological and pathological functions. Iron–sulfur proteins are one of the main reaction targets for NO, and the [Fe–S] clusters within these proteins are converted to various iron nitrosyl species upon reaction with NO...

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Bibliographic Details
Published in:Accounts of chemical research 2015-08, Vol.48 (8), p.2453-2461
Main Authors: Fitzpatrick, Jessica, Kim, Eunsuk
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacology
Biological
Cell Line
Clusters
Crystallography, X-Ray
Cysteine
Cysteine - chemistry
Cytokines - metabolism
Degradation
Formations
Hydrogen Sulfide - metabolism
Iron
Iron - chemistry
Iron-Sulfur Proteins - chemistry
Iron-Sulfur Proteins - metabolism
Macrophages - cytology
Macrophages - drug effects
Macrophages - metabolism
Mathematical models
Mice
Molecular Conformation
Nitric Oxide - metabolism
Nitrogen Oxides - chemical synthesis
Nitrogen Oxides - chemistry
Oxidation
Oxidation-Reduction
Oxygen - chemistry
Peroxynitrous Acid - chemistry
Signal Transduction
Spectrometry, Fluorescence
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Summary:Nitric oxide (NO) is an important signaling molecule that is involved in many physiological and pathological functions. Iron–sulfur proteins are one of the main reaction targets for NO, and the [Fe–S] clusters within these proteins are converted to various iron nitrosyl species upon reaction with NO, of which dinitrosyl iron complexes (DNICs) are the most prevalent. Much progress has been made in identifying the origin of cellular DNIC generation. However, it is not well-understood which other products besides DNICs may form during [Fe–S] cluster degradation nor what effects DNICs and other degradation products can have once they are generated in cells. Even more elusive is an understanding of the manner by which cells cope with unwanted [Fe–S] modifications by NO. This Account describes our synthetic modeling efforts to identify cluster degradation products derived from the [2Fe–2S]/NO reaction in order to establish their chemical reactivity and repair chemistry. Our intent is to use the chemical knowledge that we generate to provide insight into the unknown biological consequences of cluster modification. Our recent advances in three different areas are described. First, new reaction conditions that lead to the formation of previously unrecognized products during the reaction of [Fe–S] clusters with NO are identified. Hydrogen sulfide (H2S), a gaseous signaling molecule, can be generated from the reaction between [2Fe–2S] clusters and NO in the presence of acid or formal H• (e –/H+) donors. In the presence of acid, a mononitrosyl iron complex (MNIC) can be produced as the major iron-containing product. Second, cysteine analogues can efficiently convert MNICs back to [2Fe–2S] clusters without the need for any other reagents. This reaction is possible for cysteine analogues because of their ability to labilize NO from MNICs and their capacity to undergo C–S bond cleavage, providing the necessary sulfide for [2Fe–2S] cluster formation. Lastly, unique dioxygen reactivity of various types of DNICs has been established. N-bound neutral {Fe­(NO)2}10 DNICs react with O2 to generate low-temperature stable peroxynitrite (ONOO–) species, which then carry out nitration chemistry in the presence of phenolic substrates, relevant to tyrosine nitration chemistry. The reaction between S-bound anionic {Fe­(NO)2}9 DNICs and O2 results in the formation of Roussin’s red esters (RREs) and thiol oxidation products, chemistry that may be important in biological cysteine oxidati
ISSN:0001-4842
1520-4898
DOI:10.1021/acs.accounts.5b00246