title: Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin.
abstract: Nitrite reacts with deoxyhemoglobin to form nitric oxide (NO) and methemoglobin. Though this reaction is experimentally associated with NO generation and vasodilation, kinetic analysis suggests that NO should not be able to escape inactivation in the erythrocyte. We have discovered that products of the nitrite-hemoglobin reaction generate dinitrogen trioxide (N2O3) via a novel reaction of NO and nitrite-bound methemoglobin. The oxygen-bound form of nitrite-methemoglobin shows a degree of ferrous nitrogen dioxide (Fe(II)-NO2*) character, so it may rapidly react with NO to form N2O3. N2O3 partitions in lipid, homolyzes to NO and readily nitrosates thiols, all of which are common pathways for NO escape from the erythrocyte. These results reveal a fundamental heme globin- and nitrite-catalyzed chemical reaction pathway to N2O3, NO and S-nitrosothiol that could form the basis of in vivo nitrite-dependent signaling. Because the reaction redox-cycles (that is, regenerates ferrous heme) and the nitrite-methemoglobin intermediate is not observable by electron paramagnetic resonance spectroscopy, this reaction has been 'invisible' to experimentalists over the last 100 years.
authors.affiliation: Department of Physics, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, North Carolina 27109, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Basu
authors.forename: Rozalina
authors.initials: R
authors.lastname: Grubina
authors.forename: Jinming
authors.initials: J
authors.lastname: Huang
authors.forename: Jeanet
authors.initials: J
authors.lastname: Conradie
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Anne
authors.initials: A
authors.lastname: Jeffers
authors.forename: Alice
authors.initials: A
authors.lastname: Jiang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: He
authors.forename: Ivan
authors.initials: I
authors.lastname: Azarov
authors.forename: Ryan
authors.initials: R
authors.lastname: Seibert
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.forename: Rakesh
authors.initials: R
authors.lastname: Patel
authors.forename: Stephen Bruce
authors.initials: SB
authors.lastname: King
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.forename: Abhik
authors.initials: A
authors.lastname: Ghosh
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kim-Shapiro
mesh_terms: D002384:Catalysis; D004578:Electron Spin Resonance Spectroscopy; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009572:Nitrite Reductases / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D009573:Nitrites; D009589:Nitrogen Oxides; C031701:nitrogen trioxide; D007501:Iron; D009572:Nitrite Reductases; D010100:Oxygen