Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron

Abstract

Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a plethora of Fe-containing molecules. The generation of NO and CO is mediated by the nitric oxide synthase and haem oxygenase (HO) families of enzymes respectively. The effects of NO on Fe metabolism have been well characterized, whereas knowledge of the effects of CO remains within its infancy. In terms of the role of NO in Fe metabolism, one of the best characterized interactions includes its effect on the iron regulatory proteins. These molecules are mRNA-binding proteins that control the expression of the transferrin receptor 1 and ferritin, molecules that are involved in Fe uptake and storage respectively. Apart from this, activated macrophages impart their cytotoxic activity by generating NO, which results in marked Fe mobilization from tumour-cell targets. This deprives the cell of the Fe that is required for DNA synthesis and energy production. Considering that HO degrades haem, resulting in the release of CO, Fe(II) and biliverdin, it is suggested that a CO-Fe complex will form. This may account for the rapid Fe mobilization observed from macrophages after haemoglobin catabolism. Intriguingly, overexpression of HO results in cellular Fe mobilization, suggesting that CO has a similar effect to NO on Fe trafficking. Preliminary evidence suggests that, like NO, CO plays important roles in Fe metabolism.

Nitric Oxide Storage and Transport in Cells Are Mediated by Glutathione S-Transferase P1-1 and Multidrug Resistance Protein 1 via Dinitrosyl Iron Complexes

“…Many of these actions are mediated by NO binding iron in the heme group of soluble guanylate cyclase (1). The importance of iron in mediating the functions of NO is also apparent when examining its cytotoxic effects.…”

“…These effects are explained by the reactivity of NO with iron in iron-sulfur clusters, e.g. in the electron transport chain and other pools (1,3). The high affinity of NO for Fe(II) results in the interaction of NO with iron-sulfur clusters in proteins.…”

“…Nitrogen monoxide (NO) is a short lived messenger molecule that plays multiple physiological roles (1). Many of these actions are mediated by NO binding iron in the heme group of soluble guanylate cyclase (1).…”

Carbon monoxide in biological systems: an experimental and clinical study

“…When administrating CO as COHb, the amount of free CO is also increased but the local concentrations may still be too low to induce vascular responses. The interactions between CO and NO are complex (Watts et al, 2003). Perhaps when CO is administrated, less NO is produced resulting in unaltered vascular tone.…”

“…On the other hand NO can induce the expression of HO-1, which subsequently results in CO synthesis. NO that is bound to haem centres can be displaced by CO, and the liberated NO can then bind Fe released from the degradation of haem via HO (Watts, Ponka, & Richardson, 2003).…”