The effects of nitroxyl (HNO) on H2O2 metabolism and possible mechanisms of HNO signaling

Abstract

Nitroxyl (HNO) possesses unique and potentially important biological/physiological activity that is currently mechanistically ill-defined. Previous work has shown that the likely biological targets for HNO are thiol proteins, oxidized metalloproteins (i.e. ferric heme proteins) and, most likely, selenoproteins. Interestingly, these are the same classes of proteins that interact with H2O2. In fact, these classes of proteins not only react with H2O2, and thus potentially responsible for the signaling actions of H2O2, but are also responsible for the degradation of H2O2. Therefore, it is not unreasonable to speculate that HNO can affect H2O2 degradation by interacting with H2O2-degrading proteins possibly leading to an increase in H2O2-mediated signaling. Moreover, considering the commonality between HNO and H2O2 biological targets, it also seems likely that HNO-mediated signaling can also be due to reactivity at otherwise H2O2-reactive sites. Herein, it is found that HNO does indeed inhibit H2O2 degradation via inhibition of H2O2-metaboilizing proteins. Also, it is found that in a system known to be regulated by H2O2 (T cell activation), HNO behaves similarly to H2O2, indicating that HNO- and H2O2-signaling may be similar and/or intimately related.

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

“…110,156–158 Reactions of HNO with the proteins that control hydrogen peroxide degradation reveals a “cross-talk” between HNO and hydrogen peroxide that may define new redox based signaling or gene expression pathways. 159 The combination of the advances in HNO detection and donation with these emerging areas highlights the enormous potential of these new chemical biology tools to understanding HNO’s actions in biology, physiology and medicine.…”

The chemical biology of HNO signaling

“…Currently, only a few studies have examined the interaction between HNO and a selenoprotein. One study examined the ability for HNO to inhibit the selenoprotein glutathione peroxidase (GPx) [28] and reports that HNO was capable of inhibiting the activity of purified GPx under both aerobic and anaerobic conditions, with slightly more inhibition observed under aerobic conditions. Moreover, approximately 50% of the inhibition of GPx by HNO could not be reversed by the thiol reductant DTT, alluding to a significant population of an irreversibly modified adduct.…”

“…Also, since both H 2 O 2 and HNO presumably signal via electrophilic chemistry with thiols, there is a possibility that their signaling pathways are similar. Indeed, Jackson and coworkers [28] examined the relationship between H 2 O 2 and HNO and found that HNO was capable of increasing cellular levels of H 2 O 2 . Moreover, a comparison of the effects of H 2 O 2 and HNO on T-cell activation (a process reported to be regulated by H 2 O 2 ) found that they had identical signaling profiles.…”

Evaluation of nitroxyl donors' effect on mycobacteria

“…For the negative effects, in the case of Isoniazid this can be explained by the known inhibitory deleterious effect of HNO on heme proteins like catalase (the product of katG), necessary for activation of the pro-drug to its active form [24]. On the other hand, for Ethambutol it is still unclear the reason of the antagonism observed in this work and further studies are needed.…”