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

Abstract

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 oxidation. The N-bound cationic {Fe(NO)2}(9) DNICs can spontaneously release NO, and this property can be utilized in developing a new class of NO-donating agents with anti-inflammatory activity.

Nitric oxide as a developmental and metabolic signal in filamentous fungi

“…Although the gaseous radical NO has beneficial effects at low concentrations for diverse fungal physiological processes, a burst in NO production also results in a nitrosative stress due to the formation of the highly reactive nitrosonium cation (NO + ) and nitroxyl anion (NO − ). In addition, higher concentrations of cellular NO can react with oxygen species, thiol‐containing proteins and metalloproteins, leading to the inactivation of proteins necessary for physiological processes (Fitzpatrick & Kim, ). Moreover, the NO radical reacts with oxygen to produce nitrogen dioxide (NO 2 ).…”

Reactivity of a Nickel Sulfide with Carbon Monoxide and Nitric Oxide

“…18 , an observation that may have implications for our understanding of the reactions between NO and sulfur-containing metallo-proteins in vivo. 5,6 To account for the formation of 3, we hypothesize that the first step of the transformation involves sulfur abstraction by NO, forming "[K (18- Figure S14). The other products generated in the transformation remain unidentified; however, we can rule out formation of N 2 O as it could not be detected in reaction mixture by either gas chromatography or IR spectroscopy.…”

13. Reactivity of iron-sulfur clusters with nitric oxide

“…The same interconversion has been demonstrated in aqueous solvent for compounds bound to a peptide scaffold containing two cysteines [50]. Cysteine analogues have been observed to efficiently convert thiolate-bound MNICs to [2Fe-2S] clusters without the need for any other reagents, with the thiol as the source of bridging sulphide [99,100]. The thermodynamically stable RBS can be prepared directly from mononuclear DNIC species through reaction with S8 via a bis-µ-polysulfide dinitrosyl intermediate [87].…”

“…Reactions of thiolate DNICs in the presence of O2 resulted in oxidation at the sulfur centres rather than at iron with consequent formation of a RRE product and disulfide [104]. [2Fe-2S] nitrosylation in an acidic reducing environment capable of providing an e -/H + pair will lead to elimination of the bridging sulfides as H2S rather than S 0 [100] (Figure 6). H2S has been established as another key biological gasotransmitter, and redox-dependent crosstalk between H2S and NO has been proposed.…”