HNO/NO Conversion Mechanisms of Cu-Based HNO Probes with Implications for Cu,Zn-SOD

[Image: see text] HNO has broad biological effects and pharmacological activities. Direct HNO probes for in vivo applications were recently reported, which are Cu(II)-based complexes having fluorescence reporters with reaction to HNO resulting in Cu(I) systems and the release of NO. Their coordination environments are similar to that in Cu,Zn-superoxide dismutase (SOD), which plays a significant role in cellular HNO/NO conversion. However, none of these conversion mechanisms are known. A quantum chemical investigation was performed here to provide structural, energetic, and electronic profiles of HNO/NO conversion pathways via the first Cu(II)-based direct HNO probe. Results not only are consistent with experimental observations but also provide numerous structural and mechanistic details unknown before. Results also suggest the first HNO/NO conversion mechanism for Cu,Zn-SOD, as well as useful guidelines for future design of metal-based HNO probes. These results shall facilitate development of direct HNO probes and studies of HNO/NO conversions via metal complexes and metalloproteins.