{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:28:32Z","timestamp":1788456512818,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2011,5,17]],"date-time":"2011-05-17T00:00:00Z","timestamp":1305590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Chemistry A European J"],"published-print":{"date-parts":[[2011,5,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Nitrite has recently been recognized as a storage form of NO in blood and as playing a key role in hypoxic vasodilation. The nitrite ion is readily reduced to NO by hemoglobin in red blood cells, which, as it happens, also presents a conundrum. Given NO\u2019s enormous affinity for ferrous heme, a key question concerns how it escapes capture by hemoglobin as it diffuses out of the red cells and to the endothelium, where vasodilation takes place. Dinitrogen trioxide (N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub>) has been proposed as a vehicle that transports NO to the endothelium, where it dissociates to NO and NO<jats:sub>2<\/jats:sub>. Although N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub> formation might be readily explained by the reaction Hb\u2010Fe<jats:sup>3+<\/jats:sup>+NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>+NO\u21ccHb\u2010Fe<jats:sup>2+<\/jats:sup>+N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub>, the exact manner in which methemoglobin (Hb\u2010Fe<jats:sup>3+<\/jats:sup>), nitrite and NO interact with one another is unclear. Both an \u201cHb\u2010Fe<jats:sup>3+<\/jats:sup>\u2010NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>+NO\u201d pathway and an \u201cHb\u2010Fe<jats:sup>3+<\/jats:sup>\u2010NO+NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u201d pathway have been proposed. Neither pathway has been established experimentally. Nor has there been any attempt until now to theoretically model N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub> formation, the so\u2010called nitrite anhydrase reaction. Both pathways have been examined here in a detailed density functional theory (DFT, B3LYP\/TZP) study and both have been found to be feasible based on energetics criteria. Modeling the \u201cHb\u2010Fe<jats:sup>3+<\/jats:sup>\u2010NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>+NO\u201d pathway proved complex. Not only are multiple linkage\u2010isomeric (<jats:italic>N<\/jats:italic>\u2010 and <jats:italic>O<\/jats:italic>\u2010coordinated) structures conceivable for methemoglobin\u2013nitrite, multiple isomeric forms are also possible for N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub> (the lowest\u2010energy state has an N\uf8ffN\u2010bonded nitronitrosyl structure, O<jats:sub>2<\/jats:sub>N\uf8ffNO). We considered multiple spin states of methemoglobin\u2013nitrite as well as ferromagnetic and antiferromagnetic coupling of the Fe<jats:sup>3+<\/jats:sup> and NO spins. Together, the isomerism and spin variables result in a diabolically complex combinatorial space of reaction pathways. Fortunately, transition states could be successfully calculated for the vast majority of these reaction channels, both <jats:italic>M<\/jats:italic><jats:sub>S<\/jats:sub>=0 and <jats:italic>M<\/jats:italic><jats:sub>S<\/jats:sub>=1. For a six\u2010coordinate Fe<jats:sup>3+<\/jats:sup>\u2010<jats:italic>O<\/jats:italic>\u2010nitrito starting geometry, which is plausible for methemoglobin\u2013nitrite, we found that N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub> formation entails barriers of about 17\u201320\u2005kcal\u2009mol<jats:sup>\u22121<\/jats:sup>, which is reasonable for a physiologically relevant reaction. For the \u201cHb\u2010Fe<jats:sup>3+<\/jats:sup>\u2010NO+NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u201d pathway, which was also found to be energetically reasonable, our calculations indicate a two\u2010step mechanism. The first step involves transfer of an electron from NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup> to the Fe<jats:sup>3+<\/jats:sup>\u2013heme\u2013NO center ({FeNO}<jats:sup>6<\/jats:sup>) , resulting in formation of nitrogen dioxide and an Fe<jats:sup>2+<\/jats:sup>\u2013heme\u2013NO center ({FeNO}<jats:sup>7<\/jats:sup>). Subsequent formation of N<jats:sub>2<\/jats:sub>O<jats:sub>3<\/jats:sub> entails a barrier of only 8.1\u2005kcal\u2009mol<jats:sup>\u22121<\/jats:sup>. From an energetics point of view, the nitrite anhydrase reaction thus is a reasonable proposition. Although it is tempting to interpret our results as favoring the \u201c{FeNO}<jats:sup>6<\/jats:sup>+NO<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u201d pathway over the \u201cFe<jats:sup>3+<\/jats:sup>\u2010nitrite+NO\u201d pathway, both pathways should be considered energetically reasonable for a biological reaction and it seems inadvisable to favor a unique reaction channel based solely on quantum chemical modeling.<\/jats:p>","DOI":"10.1002\/chem.201003578","type":"journal-article","created":{"date-parts":[[2011,5,17]],"date-time":"2011-05-17T07:02:20Z","timestamp":1305615740000},"page":"6348-6358","source":"Crossref","is-referenced-by-count":40,"title":["Hemoglobin as a Nitrite Anhydrase: Modeling Methemoglobin<i>\u2010<\/i>Mediated N<sub>2<\/sub>O<sub>3<\/sub> Formation"],"prefix":"10.1002","volume":"17","author":[{"given":"Kathrin H.","family":"Hopmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Cardey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Gladwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B.","family":"Kim\u2010Shapiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhik","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,5,17]]},"reference":[{"key":"e_1_2_6_1_2","first-page":"1","volume-title":"Nitric Oxide: Biology and Pathobiology","year":"2010"},{"key":"e_1_2_6_2_2","first-page":"1","volume-title":"The Smallest Biomolecules: Diatomics and Their Interactions with Heme Proteins","year":"2008"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1039\/9781847551238"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2009.12.142"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm954"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-373866-0.00019-8"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24650"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2466"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806654200"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2003.11.032"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.17.8137"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2007.46"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2006.01.012"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.F292"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpb.2005.04.016"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2004.01.004"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja036693b"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic0603104"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic020519r"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp909425z"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja903364h"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2009.11.003"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi801104c"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi801015c"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/38775"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi7021415"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0206487"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic901722g"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0567891"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja904726q"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic035403p"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2006.04.011"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevA.38.3098"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevB.37.785"},{"key":"e_1_2_6_35_2","unstructured":"Gaussian\u200503 Revision\u2005E.01 M.\u2005J. 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Without solvent the Gibbs free energies are 11.7\u2005kcal\u2009mol\u22121for the TS and 9.3\u2005kcal\u2009mol\u22121for the product."},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic700846x"},{"key":"e_1_2_6_46_2","unstructured":"Solvent\u2010corrections could not be applied to the relative energies for modelC because the necessary open\u2010shell character of the transition state could not be preserved in single\u2010point IEFPCM calculations on the optimized geometries."},{"key":"e_1_2_6_47_2","first-page":"5","volume-title":"Nitrosation Reactions and the Chemistry of Nitric Oxide","author":"Williams D. L. 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