The chemical biology of HNO signaling

Abstract

Nitroxyl (HNO) is a simple molecule with significant potential as a pharmacological agent. For example, its use in the possible treatment of heart failure has received recent attention due to its unique therapeutic properties. Recent progress has been made on the elucidation of the mechanisms associated with its biological signaling. Importantly, the biochemical mechanisms described for HNO bioactivity are consistent with its unique and novel chemical properties/reactivity. To date, much of the biology of HNO can be associated with interactions and modification of important regulatory thiol proteins. Herein will be provided a description of HNO chemistry and how this chemistry translates to some of its reported biological effects.

Synthesis and HNO Donating Properties of the Piloty's Acid Analogue Trifluoromethanesulphonylhydroxamic Acid: Evidence for Quantitative Release of HNO at Neutral pH Conditions

“…Nitroxyl (azanone, nitroxyl hydride, HNO) has gained increasing attention owing to a growing number of reports describing its biological activity. The properties of HNO show some similarities to those of its redox sibling NO, but major differences are also observed . In particular, HNO is showing promise for treating heart failure .…”

“…In particular, HNO is showing promise for treating heart failure . Although HNO has been the subject of extensive experimental and theoretical analysis, there remains much to learn about its chemistry, reactivity and biological activity. One of the main challenges in studying the reactivity of HNO is its rapid dimerization to nitrous oxide and water in aqueous solution ( k =8×10 6 m −1 s −1 ) .…”

The Roles of NO and H2S in Sperm Biology: Recent Advances and New Perspectives

“…Using a HNO donor (Angeli's salt), Andrews et al [131] demonstrated for the first time that it acts through the sGC/cGMP pathway. HNO also protects PUFA from peroxidation due to its antioxidant properties [132]. The protective ability of HNO should also be considered in the case of the sperm plasma membrane, as it contains a high amount of PUFA [73].…”

“…The protective ability of HNO should also be considered in the case of the sperm plasma membrane, as it contains a high amount of PUFA [73]. On the other hand, HNO can increase intracellular levels of H 2 O 2 by inhibiting its degradation, and it also reacts with thiol proteins, such as GAPDH, decreasing its activity [132,133]. Sperm-specific GAPDH (GAPDS) is particularly important in sperm cell energetic metabolism [68].…”

Modeling of S‐Nitrosothiol–Thiol Reactions of Biological Significance: HNO Production by S‐Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates

“…Nitric oxide (NO) is an important signaling molecule that plays a key role in numerous physiological processes, such as vasodilation, immune response, neuronal signaling, etc . The reduced form of nitric oxide, HNO/NO − , usually referred to as nitroxyl, exhibits its own unique biological activity and has significant pharmacological potential. For instance, HNO can act as a positive cardiac inotrope and lusitrope that provides great promise in the treatment of heart failure; also, as nitroxyl inhibits aldehyde dehydrogenase, it has potential as an alcoholism treatment .…”