Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin

Swati Basu, Rozalina Grubina, Jinming Huang, Jeanet Conradie, Zhi Huang, Anne Jeffers, Alice Jiang, Xiaojun He, Ivan Azarov, Ryan Seibert, Atul Mehta, Rakesh Patel, Stephen Bruce King, Neil Hogg, Abhik Ghosh, Mark T. Gladwin, Daniel B. Kim-Shapiro

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


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 (N 2O3) 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. N 2O3 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.

Original languageEnglish (US)
Pages (from-to)785-794
Number of pages10
JournalNature Chemical Biology
Issue number12
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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