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The complete reaction undergoes a three\u2010step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.5\u2005kcal\u2009mol<jats:sup>\u22121<\/jats:sup>, which is consistent with that described for <jats:italic>Escherichia coli<\/jats:italic> glutamine synthetase (15\u201317\u2005kcal\u2009mol<jats:sup>\u22121<\/jats:sup>). The participating active site residues have been identified and their role and energy contributions clarified. This study provides an insightful atomic description of the biosynthetic reaction that takes place in this enzyme, opening doors for more accurate studies for developing new anti\u2010tuberculosis therapies.<\/jats:p>","DOI":"10.1002\/chem.201600305","type":"journal-article","created":{"date-parts":[[2016,5,25]],"date-time":"2016-05-25T20:22:21Z","timestamp":1464207741000},"page":"9218-9225","source":"Crossref","is-referenced-by-count":19,"title":["Reaction Mechanism of <i>Mycobacterium Tuberculosis<\/i> Glutamine Synthetase Using Quantum Mechanics\/Molecular Mechanics Calculations"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6904-2511","authenticated-orcid":false,"given":"C\u00e1tia","family":"Moreira","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  4169-007 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7554-8324","authenticated-orcid":false,"given":"Maria J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  4169-007 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-4722","authenticated-orcid":false,"given":"Pedro Alexandrino","family":"Fernandes","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  4169-007 Porto Portugal"}]}],"member":"311","published-online":{"date-parts":[[2016,5,25]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.2.476"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.03.015"},{"key":"e_1_2_6_4_1","unstructured":"\u00a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/jexbot\/53.370.979"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8137.2009.02823.x"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026234014816"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095939"},{"key":"e_1_2_6_9_1","unstructured":"\u00a0"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.10.6348-6363.2001"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.4.2412-2415.2004"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi020254s"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2008.04.015"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502248102"},{"key":"e_1_2_6_15_1","unstructured":"\u00a0"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.20.9342"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/286079a0"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444912048998"},{"key":"e_1_2_6_19_1","unstructured":"\u00a0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2009.06.045"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/1087057105278013"},{"key":"e_1_2_6_22_1","unstructured":"R. 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