TY - JOUR
T1 - Catalytic generation of N2O3 by the concerted nitrite reductase and anhydrase activity of hemoglobin
AU - Basu, Swati
AU - Grubina, Rozalina
AU - Huang, Jinming
AU - Conradie, Jeanet
AU - Huang, Zhi
AU - Jeffers, Anne
AU - Jiang, Alice
AU - He, Xiaojun
AU - Azarov, Ivan
AU - Seibert, Ryan
AU - Mehta, Atul
AU - Patel, Rakesh
AU - King, Stephen Bruce
AU - Hogg, Neil
AU - Ghosh, Abhik
AU - Gladwin, Mark T.
AU - Kim-Shapiro, Daniel B.
N1 - Funding Information:
We thank D.L.H. Williams for helpful discussion and for his seminal and pioneering work in nitrosation chemistry. This work was supported by US National Institutes of Health (NIH) grants HL58091 (D.B.K.-S.), GM55792 (N.H.) and HL62198 (S.B.K.). EPR spectrometry was facilitated by a grant from the North Carolina Biotechnology Center (2003-IDG-1013, D.B.K.-S.). D.B.K.-S. gratefully acknowledges further support from NIH grant K02 HL078706. A.G. thanks the Research Council of Norway for supercomputing time, and J.C. thanks the South African National Research Foundation for further support. M.T.G. is supported by the Division of Intramural Research of the US National Heart, Lung, and Blood Institute.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.2007.46
DO - 10.1038/nchembio.2007.46
M3 - Article
C2 - 17982448
AN - SCOPUS:36248985678
SN - 1552-4450
VL - 3
SP - 785
EP - 794
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 12
ER -