Carbon Monoxide Promotes Respiratory Hemoproteins Iron Reduction Using Peroxides as Electron Donors

Abstract

The physiological role of the respiratory hemoproteins (RH), hemoglobin and myoglobin, is to deliver O2 via its binding to their ferrous (FeII) heme-iron. Under variety of pathological conditions RH proteins leak to blood plasma and oxidized to ferric (FeIII, met) forms becoming the source of oxidative vascular damage. However, recent studies have indicated that both metRH and peroxides induce Heme Oxygenase (HO) enzyme producing carbon monoxide (CO). The gas has an extremely high affinity for the ferrous heme-iron and is known to reduce ferric hemoproteins in the presence of suitable electron donors. We hypothesized that under in vivo plasma conditions, peroxides at low concentration can assist the reduction of metRH in presence of CO. The effect of CO on interaction of metRH with hydrophilic or hydrophobic peroxides was analyzed by following Soret and visible light absorption changes in reaction mixtures. It was found that under anaerobic conditions and low concentrations of RH and peroxides mimicking plasma conditions, peroxides served as electron donors and RH were reduced to their ferrous carboxy forms. The reaction rates were dependent on CO as well as peroxide concentrations. These results demonstrate that oxidative activity of acellular ferric RH and peroxides may be amended by CO turning on the reducing potential of peroxides and facilitating the formation of redox-inactive carboxyRH. Our data suggest the possible role of HO/CO in protection of vascular system from oxidative damage.

Handling heme: The mechanisms underlying the movement of heme within and between cells

“…Similarly, little is known about the effect of CO on heme trafficking. Given the high affinity of CO for 5-or 6-coordinate ferrous hemoproteins, [141,142] CO binding may prevent heme oxidation and subsequent dissociation, [143] which would result in less labile or bioavailable heme ( Figure 5F).…”

Biological signaling by carbon monoxide and carbon monoxide-releasing molecules

“…Nevertheless, another critical task carried out by CO appears to be directly related to its ability to prevent heme oxidation once bound to the ferrous form of the molecule, which has relevance for normal and pathological conditions and may be a unique characteristic of CO due its exclusive binding to the reduced form of iron. In biochemical investigations in which this precise hypothesis was investigated, Sher and colleagues (103) showed how, in the presence of low concentrations of Hb or Mb and peroxides mimicking those found in plasma, the ferric forms of the proteins were converted by CO to the ferrous carboxy forms. This reaction depends on peroxides as the source of electrons for the reduction and is expected to occur in cell-free Hb, which is susceptible to oxidation once outside the red blood cell.…”

The Protective Role of Carbon Monoxide (CO) Produced by Heme Oxygenases and Derived from the CO-Releasing Molecule CORM-2 in the Pathogenesis of Stress-Induced Gastric Lesions: Evidence for Non-Involvement of Nitric Oxide (NO)

“…Sensing gaseous molecules such as oxygen (O 2 ), nitric oxide (NO) and CO are distinctive features of living organisms and are predominantly mediated by heme-based sensors [ 4 ]. Most of the actions of CO are exerted through the binding of CO to ferrous iron (Fe 2+ ) and subsequent alteration of the functions of the hemoproteins [ 5 , 6 ]. CO competes with O 2 for metalloproteins such as hemoglobin (Hb), myoglobin, cytochrome c oxidase and cytochrome P-450 [ 7 , 8 ].…”