title: Concerted nitric oxide formation and release from the simultaneous reactions of nitrite with deoxy- and oxyhemoglobin.
abstract: 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.
authors.affiliation: Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Rozalina
authors.initials: R
authors.lastname: Grubina
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Joshi
authors.forename: Ivan
authors.initials: I
authors.lastname: Azarov
authors.forename: Swati
authors.initials: S
authors.lastname: Basu
authors.forename: Lorna A
authors.initials: LA
authors.lastname: Ringwood
authors.forename: Alice
authors.initials: A
authors.lastname: Jiang
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kim-Shapiro
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: 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
chemical_list: D006454:Hemoglobins; D009573:Nitrites; D010108:Oxyhemoglobins; D009569:Nitric Oxide; C100003:deoxyhemoglobin; D008706:Methemoglobin; D009572:Nitrite Reductases; D010100:Oxygen