Chemical Biology of Nitroxyl (HNO)

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

HNO the redox sibling of NO biology and potential impact in cancer and cardiac/cardiovascular biology. Our group has been interested in the differential biological properties of NO and other RNS. One of the long-standing interests is in differences of HNO and NO and their biological properties. While separate by only one electron the chemical properties between HNO and NO due to high pKa and spin forbidden transition preclude facile interconversion between HNO and NO thus allowing interaction with the biological targets to be unique (PMID: 12855429; PMID: 15822180). This orthogonality is demonstrated in different impact on different effect. For example, discussed above NO can promote cancer progression and even protect cells. In contrast HNO, can selectively target tumor cells versus normal cells. Development by Miranda and coworkers HNO NSAIDs were found to have potent anticancer properties while increase the gastric safety by 40 times of aspirin (PMID: 25153034). One of the most profound effects in the cardiac where Dr. Nazerrano Paolocci et al. (patent Wink et al.) showed that HNO donors had powerful and selective positive inotropic and luscitropic improving cardiac output even under heart failure conditions (PMID: 11517312; PMID: 12704230). Clinical trials with HNO donors in heart failure showed increase in cardiac output in patients with acute heart failure (PMID: 33248986; PMID: 30703258). In addition, HNO was shown in contrast to NO to preferential dilate venular side of the vascular thus off-loading the heart in a canine model. HNO and NO also have different effects in cardiac ischemia reperfusion where after infarct NO had beneficial impact while HNO increased invasive neutrophils enlarging the area (PMID: 10588754). However, HNO was found to precondition the heart to be resistant similar to pre-hypoxia (PMID: 12498977) through inhibiting the mPTP Opening via PKC Activation (PMID: 35204265). These results suggest that HNO compounds could have powerful impact. In cardiovascular Kemp Harper showed that HNO had unique properties similar to that of the endothelial hyperpolarization factor which reduce hypertension (PMID: 17309955). In addition, HNO and NO differential regulate neuronal glutamate channels such the NMDA channel. Careful use of HNO and NO donors show that these species have different effect on a number of channels. The chemical reactivity differential between HNO and NO the explanation of their unique set of biological effects. Identification of the rate constants for with Dr. Fukuto and Miranda show the high kinetic/thermodynamic barrier between the interconversions and very slow reaction allows other reaction in biological (PMID: 12865500; PMID: 15822180;PMID: 19727606). One of the major difference is between HNO facile reaction with thiols and zn fingers. Where NO has to be converted to N2O3 and even NO2 prior to reaction with RSH is relative slow. NO perfences for reduced metals like ferrous, HNO favors ferric containing. These have relevance in that in high thiol regions like GSH in cytoplasm HNO is unlike to hit many thiols target (except with high pKa) while NO can diffuse to hit other targets in cytoplasm. Thus, there spatial profiles and diffusion are expected to be different. The biochemical formation has been examined using the unique formation of sulfenamide as well NH2OH. There are three conditions that HNO formation: nitrosation of from formation RSNO followed by another to form HNO and disulfide. Protein with cis sulfhydryl such lipoic acid or proteins such as TRX and Prx lead to HNO from N2O3 (PMID: 16540401). Recently Palmieri et al. showed for the first time that HNO was formed in lipoate requiring enzyme PDH resulting in inhibition E3 ligase and inhibition of the capacity of pyruvate to be taken into the Kreb cycle (PMID: 37607904). This demonstrates the unique specificity of HNO targeting neighboring proteins and a non-radical method for reactive species to inhibit specific targets. Acidic condition found in phagosomes and lysosomes with nitrite leading to NO/N2O3/NO2 can lead to nitrosation of thiols that decompose to HNO. Subsequent reaction of HNO with other thiols lead to NH2OH. NH2OH can be recycle to HNO through was reaction of peroxide heme proteins (nonheme) and NH2OH to HNO. Reaction with HNO and thiols recycle NH2OH providing a method oxidize thiols. Unique phosphine probes develop by Dr. Bruce King provide a valuable tool to elucidated to HNO biology.