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Nitric Oxide, Sepsis and the Heart
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Louis H. Alarcon, Timothy R. Billiar, Richard L. Simmons
NO produces a wide range of effects in different cells and tissues. NO interacts with targets via covalent (additive) and non-covalent (redox) reactions. Thus, both nitrosation of peptides and oxidation events that do not involve the attachment of the nitroso group are mechanisms of action of this versatile messenger. In biologic systems, NO readily reacts with oxygen (O2), superoxide (O2−), and transition metals, producing NOx, peroxynitrite (OONO), and metalo-NO adducts, respectively. These products can also produce nitrosative reactions at nucleophilic centers (Stamler, Singel and Loscalzo, 1992; Mohr, Stamler and Brune, 1994). The greater prevalence and reactivity of thiol groups explain the propensity for S-nitrosothiol (RS-NO) formation. Thus, metal- and thiol-containing proteins serve as major target sites for NO; these include signaling proteins, ion channels, receptors, enzymes and transcription factors (Table 5-3). An important heme-containing protein, soluble guanylate cyclase, undergoes a structural change upon NO binding. The enzyme becomes activated, producing cyclic guanosine monophosphate (cGMP), which mediates many of the target cell responses to NO, including vasorelaxation and inhibition of platelet aggregation.
Glutathione Release and Nitrosoglutathione Presence in the CNS: Implications for Schizophrenia
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
The physiological significance of this nitrosothiol in the CNS is yet unknown. GSNO has been used widely as a NO donor, and it is the most potent activator of guanylate cyclase (Garthwaite 1993). Whether endogenous GSNO acts through release of the fiee radical NO* or independently of the latter has yet to be determined. In support of the first possibility, GSNO may play a role as a more stable carrier for the radical NO* that can freely cross the cell membrane and can act on soluble guanylate cyclase in the target cell. However, the presence in rat brain of a specific [3H]GSNO binding site (Taguchi, Ohta, and Talman 1995) favors the second possibility, where endogenous GSNO may bind to the target cell membrane and elicit its activity per se. Another possibility is that GSNO, through the transfer or reaction of NO+, may nitrosylate sulfhydryl centers of proteins such as key enzymes or receptors (Meffert et al. 1996) in the target cell. Moreover, a neuroprotective antioxidative effect has been found for GSNO when injected in vivo in rat striatum (Rauhala et al. 1996).
Nitric Oxide as a Mediator of Intestinal Mucosal Function
Published in T. S. Gaginella, Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Mark J. S. Miller, Timothy S. Gaginella
High concentration of NO can lead to the formation of novel molecular species (N2O3, N2O4) that require second-order kinetics. These products can cause cellular dysfunction through nitration of key enzymes and may cause point DNA mutations. Thiols are also a key site of NO-based interactions (Figure 1). Nitric oxide has strong avidity for thiol groups, resulting in nitrosothiol formation. This may compromise the function of enzymes, free heavy metals (e.g., from metallothionein) or limit antioxidant capabilities. Disulfide bonds may also be disrupted, greatly influencing the function of key proteins.
Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Anna Di Fiore, Claudiu T. Supuran, Andrea Scaloni, Giuseppina De Simone
Protein S-nitrosylation, the oxidative modification of cysteine residues by nitric oxide (NO) to form S-nitrosothiols, modifies a number of proteins, also in their activity, and provides a fundamental redox-based cellular signalling mechanism76,77. Differently from other PTMs, it is generally considered to be non-enzymatic and may involve multiple chemical routes for its accomplishment. In agreement with preliminary evidences reporting S-nitrosylation of CA III in rat liver78, this isozyme is the only protein reported to be affected by this PTM (Figure 2), which occurs at C6679. This residue is not accessible on the protein surface but, probably being highly reactive, can be easily reached by small-size S-nitrosylating molecules, such as NO and SNOs. It localises close to proton shuttle residue (K64); this suggests that this modification may eventually affect the enzyme activity. Accordingly, novel studies are encouraged to investigate the role of S-nitrosylation in controlling CA III catalysis, and the participation of this isozyme in redox-based cellular signalling mechanisms, as already observed for other CAs in plants80,81.
S-Nitrosoglutathione formation at gastric pH is augmented by ascorbic acid and by the antioxidant vitamin complex, Resiston
Published in Pharmaceutical Biology, 2018
Vitali I. Stsiapura, Ilya Bederman, Ivan I. Stepuro, Tatiana S. Morozkina, Stephen J. Lewis, Laura Smith, Benjamin Gaston, Nadzeya Marozkina
Here, we have focused on the effect of AA on the GSNO concentration because it is an essential vitamin and reducing agent present in many foods, and is used ubiquitously in the nutraceutical industry as an orally ingested electron donor (‘nutritional antioxidant’). It is well known that presence of AA promotes decomposition of GSNO and other S-nitrosothiols at physiological pH; this reaction is widely used to measure S-nitrosothiol concentrations (Paige et al. 2008). Reaction of AA with S-nitrosothiols was studied earlier (Holmes and Williams 2000; Paige et al. 2008; Melzer et al. 2012) and two reaction pathways were identified. The first one dominates at low concentration of AA and is Cu2+ dependent and the second route becomes important at higher concentrations of AA and is [Cu2+]-independent. The first mechanism involves reduction of Cu2+ ions by AA to form Cu+ which further donates electron to GSNO resulting in NO and GSH production.
Nitrous anhydrase activity of carbonic anhydrase II: cysteine is required for nitric oxide (NO) dependent phosphorylation of VASP in human platelets
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Dimitrios Tsikas, Stepan Gambaryan
A sophisticated animal study was performed by Wang et al.14. In CA II+/+, CA II ± and CA II-/- mice (26 − 32 g body weight), infusion of NaNO2 (30, 50, 100, 500, 2500 nmol over 5 min corresponding to doses of up to 3.8 mg nitrite/kg body weight) lowered mean arterial blood pressure equally from about 70 mmHg down to 40 mmHg in CA II+/+, CA II ± and CA II-/-, suggesting a mechanism independent of CA II14. Unfortunately, the authors did not report on the possible formation of S-nitrosothiols, which could have been an indication of hCA II involvement. It is worth mentioning that increase in plasma S-nitrosothiol concentration was observed upon iNaNO2 for 10 min in doses of 0.06 to 2.2 mg NaNO2/kg body weight in healthy subjects37. Our group provided unequivocal evidence of the formation of 15 N-labelled S-nitrosoglutathione (GS15NO) from 15 N-labelled nitrite and GSH by means of a commercially available recombinant human erythrocytic CA II (heCA II) in Tris buffer at pH 7.4 in the absence of externally added bicarbonate2. In washed human platelets, the activity of sGC upon incubation with 100 µM nitrite, 20 mM bicarbonate and bovine erythrocytic CA II was comparable with that observed with 1 µM S-nitrosocysteine (CysSNO), one of the strongest endogenous inhibitors of platelet aggregation29. In the present study, comparable effects were obtained with 10 µM nitrite and 100 µM L-cysteine. This may suggest that 10 µM nitrite/100 µM L-cysteine is about 10 less active that SNP regarding NO formation.