Reactions between nitric oxide and haemoglobin under physiological conditions

Abstract

The tenet of high-affinity nitric oxide (NO) binding to a haemoglobin (Hb) has shaped our view of haem proteins and of small diffusible signaling molecules. Specifically, NO binds rapidly to haem iron in Hb (k approximately 10[7] M[-1] s[-1]) and once bound, the NO activity is largely irretrievable (Kd approximately 10[-5] s[-1]); the binding is purportedly so tight as to be unaffected by O2 or CO. However, these general principles do not consider the allosteric state of Hb or the nature of the allosteric effector, and they mostly derive from the functional behaviour of fully nitrosylated Hb, whereas Hb is only partially nitrosylated in vivo. Here we show that oxygen drives the conversion of nitrosylhaemoglobin in the 'tense' T (or partially nitrosylated, deoxy) structure to S-nitrosohaemoglobin in the 'relaxed' R (or ligand-bound, oxy) structure. In the absence of oxygen, nitroxyl anion (NO-) is liberated in a reaction producing methaemoglobin. The yields of both S-nitrosohaemoglobin and methaemoglobin are dependent on the NO/Hb ratio. These newly discovered reactions elucidate mechanisms underlying NO function in the respiratory cycle, and provide insight into the aetiology of S-nitrosothiols, methaemoglobin and its related valency hybrids. Mechanistic reexamination of NO interactions with other haem proteins containing allosteric-site thiols may be warranted.

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…Indeed, several proteins involved in Ca 2+ and redox signaling are known to be modified by S-nitrosation, including L-type Ca 2+ channels [77], ryanodine receptors [78], thioredoxin [79] hemoglobin [80], mitochondrial K + ATP channels [81,82], TRP channels [83], and caspases [26]. The relative importance of complex I as a mediator of the cardioprotective effects of NO • remains to be determined.…”

Hemoglobin is expressed in alveolar epithelial type II cells

“…Hemoglobin is also thought to be involved in the protection of cells against nitrosative stress [15;16]. Recent studies have shown that hemoglobin can bind and release NO as a redox reaction, thus functioning in close resemblance to cytochromes [17]. Neuroglobin and cytoglobin, two other members of the vertebrate globin family, also have protective functions including oxygen sensing and scavenging [9;13;14].…”

Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity

“…Recent work by Stamler and colleagues (6)(7)(8) suggests that NO binding to hemoglobin may play a role in the regulation of vascular tone, with NO binding and release tied to oxygen-induced allosteric structural transitions. In the lungs, hemoglobin is highly saturated with oxygen, and NO produced in the lungs is thought to bind to cysteine 93 on the β chain.…”