Concerted nitric oxide formation and release from the simultaneous reactions of nitrite with deoxy- and oxyhemoglobin.
Recent studies reveal a novel role for hemoglobin as an allosterically regulated nitrite reductase that may mediate nitric oxide (NO)-dependent signaling along the physiological oxygen gradient. Nitrite reacts with deoxyhemoglobin in an allosteric reaction that generates NO and oxidizes deoxyhemoglobin to methemoglobin. NO then reacts at a nearly diffusion-limited rate with deoxyhemoglobin to form iron-nitrosyl-hemoglobin, which to date has been considered a highly stable adduct and, thus, not a source of bioavailable NO. However, under physiological conditions of partial oxygen saturation, nitrite will also react with oxyhemoglobin, and although this complex autocatalytic reaction has been studied for a century, the interaction of the oxy- and deoxy-reactions and the effects on NO disposition have never been explored. We have now characterized the kinetics of hemoglobin oxidation and NO generation at a range of oxygen partial pressures and found that the deoxy-reaction runs in parallel with and partially inhibits the oxy-reaction. In fact, intermediates in the oxy-reaction oxidize the heme iron of iron-nitrosyl-hemoglobin, a product of the deoxy-reaction, which releases NO from the iron-nitrosyl. This oxidative denitrosylation is particularly striking during cycles of hemoglobin deoxygenation and oxygenation in the presence of nitrite. These chemistries may contribute to the oxygen-dependent disposition of nitrite in red cells by limiting oxidative inactivation of nitrite by oxyhemoglobin, promoting nitrite reduction to NO by deoxyhemoglobin, and releasing free NO from iron-nitrosyl-hemoglobin.
Grubina
Rozalina
R
Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Huang
Zhi
Z
Shiva
Sruti
S
Joshi
Mahesh S
MS
Azarov
Ivan
I
Basu
Swati
S
Ringwood
Lorna A
LA
Jiang
Alice
A
Hogg
Neil
N
Kim-Shapiro
Daniel B
DB
Gladwin
Mark T
MT
D000818:Animals; D004912:Erythrocytes / Q000737:chemistry* / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism; D006736:Horses; D006801:Humans; D008706:Methemoglobin / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000737:chemistry* / Q000378:metabolism; D009572:Nitrite Reductases / Q000737:chemistry* / Q000378:metabolism; D009573:Nitrites / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D010108:Oxyhemoglobins / Q000737:chemistry* / Q000378:metabolism
D006454:Hemoglobins; D009573:Nitrites; D010108:Oxyhemoglobins; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D008706:Methemoglobin; D009572:Nitrite Reductases; D010100:Oxygen