Lewis Acid Coordination Redirects S-Nitrosothiol Signaling Output

Area of Science:

• Chemical Biology
• Bioinorganic Chemistry
• Organic Chemistry

Background:

• S-Nitrosothiols (RSNOs) are crucial biological reservoirs for nitric oxide (NO).
• Copper enzymes facilitate NO release from RSNOs via Lewis acid catalysis and intramolecular electron transfer.
• Separating Lewis acid coordination from redox activity allows for a clearer understanding of RSNO structure and reactivity.

Purpose of the Study:

• To investigate the effect of a redox-innocent Lewis acid, B(C6F5)3, on the electronic structure and reactivity of RSNOs.
• To explore the potential for Lewis acid coordination to modulate the reduction potential of RSNOs.
• To elucidate the mechanism of NO release from RSNOs mediated by Lewis acid coordination.

Main Methods:

• Coordination of B(C6F5)3 to the oxygen atom of RSNOs.
• Electrochemical studies to determine reduction potentials.
• Outer-sphere chemical reduction experiments.
• Mechanistic and computational studies (e.g., DFT) to support proposed pathways.

Main Results:

• B(C6F5)3 coordination to RSNOs causes significant changes in their electronic structure and reactivity.
• Lewis acid coordination increases RSNO reduction potentials by over 1 V, making them physiologically accessible (+0.1 V vs. NHE).
• Outer-sphere reduction yields a Lewis acid-stabilized hyponitrite dianion, which releases N2O upon acidification.
• Mechanistic studies suggest initial reduction to a radical anion, followed by N-N coupling and RSSR loss.

Conclusions:

• Redox-innocent Lewis acids can effectively modulate the electrochemical properties of RSNOs.
• Lewis acid coordination offers a strategy to tune RSNO reduction potentials for biological applications.
• The study reveals a novel pathway for RSNO decomposition involving Lewis acid stabilization of intermediates.