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The GP catalytic mechanism has been explored by quantum mechanics\/molecular mechanics (QM\/MM) methods. Herein, we propose a mechanism that proceeds by three steps: 1)\u2005it begins with transfer of a hydrogen atom from the phosphate group of the pyridoxal 5\u2032\u2010phosphate (HPO<jats:sub>4<\/jats:sub><jats:sup>2\u2212<\/jats:sup>\u2010PLP) cofactor to the phosphate substrate; 2)\u2005the glycosidic linkage is then cleaved through protonation of the glycosidic oxygen atom by a hydroxy group of the inorganic phosphate group; and 3)\u2005an oxygen atom of the phosphate performs a nucleophilic attack on the anomeric carbon atom of glucose, concomitant with the return of a proton from phosphate to PO<jats:sub>4<\/jats:sub><jats:sup>3\u2212<\/jats:sup>\u2010PLP, which finally leads to formation of the glucose\u20101\u2010phosphate product and recovers the initial state of the PLP cofactor. The glycosidic bond cleavage and nucleophilic attack from the phosphate group to the glycosyl molecule have the highest activation free energies. The structural properties of the hereby characterized transition states could be very useful in structure\u2010based drug design studies against liver GP.<\/jats:p>","DOI":"10.1002\/cmdc.201800218","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T14:07:16Z","timestamp":1529071636000},"page":"1608-1616","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Understanding the Rate\u2010Limiting Step of Glycogenolysis by Using QM\/MM Calculations on Human Glycogen Phosphorylase"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3130-9807","authenticated-orcid":false,"given":"Nat\u00e9rcia F.","family":"Br\u00e1s","sequence":"first","affiliation":[{"name":"REQUIMTE\/UCIBIO, Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre s\/n 4169-007 Porto Portugal"}]},{"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"REQUIMTE\/UCIBIO, Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre s\/n 4169-007 Porto Portugal"}]},{"given":"Maria J.","family":"Ramos","sequence":"additional","affiliation":[{"name":"REQUIMTE\/UCIBIO, Departamento de Qu\u00edmica e Bioqu\u00edmica Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre s\/n 4169-007 Porto Portugal"}]}],"member":"311","published-online":{"date-parts":[[2018,7,10]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2013.11.002"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1099-0895(1998090)14:3<207::AID-DMR214>3.0.CO;2-J"},{"key":"e_1_2_7_3_1","unstructured":"\u00a0"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986708786848659"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2013.794790"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2016.1131268"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi960072w"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.6.6.1544539"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi702397d"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-050511-102222"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(05)00006-7"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.2174\/138955706777934991"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20939"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.12.3716"},{"key":"e_1_2_7_15_1","unstructured":"\u00a0"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct900530f"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.carres.2014.06.017"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.061005.092322"},{"key":"e_1_2_7_19_1","unstructured":"\u00a0"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2680317"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2394"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410468200"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar970172"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20396"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b01156"},{"key":"e_1_2_7_26_1","unstructured":"\u00a0"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867322666150821100851"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.5b00002"},{"key":"e_1_2_7_29_1","unstructured":"\u00a0"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.8.2453"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.4.1776"},{"key":"e_1_2_7_32_1","unstructured":"\u00a0"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/cs500093h"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201601670"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5CP06224A"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1281"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21837"},{"key":"e_1_2_7_38_1","unstructured":"\u00a0"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00430a024"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)41971-5"},{"key":"e_1_2_7_41_1","unstructured":"N.\u2005F. 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