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Given that the release of G6P in the gluconeogenesis raises the glucose output levels, \u03b1\u2010PGM represents a tempting pharmacological target for type\u20052 diabetes. Here, we provide the first theoretical study of the catalytic mechanism of human \u03b1\u2010PGM. We performed transition\u2010path sampling simulations to unveil the atomic details of the two catalytic chemical steps, which could be key for developing transition state (TS) analogue molecules with inhibitory properties. Our calculations revealed that both steps proceed through a concerted S<jats:sub>N<\/jats:sub>2\u2010like mechanism, with a loose metaphosphate\u2010like TS. Even though experimental data suggests that the two steps are identical, we observed noticeable differences: 1)\u2005the transition state ensemble has a well\u2010defined TS region and a late TS for the second step, and 2)\u2005larger coordinated protein motions are required to reach the TS of the second step. We have identified key residues (Arg23, Ser117, His118, Lys389), and the Mg<jats:sup>2+<\/jats:sup> ion that contribute in different ways to the reaction coordinate. Accelerated molecular dynamics simulations suggest that the G16P intermediate may reorient without leaving the enzymatic binding pocket, through significant conformational rearrangements of the G16P and of specific loop regions of the human \u03b1\u2010PGM.<\/jats:p>","DOI":"10.1002\/chem.201705090","type":"journal-article","created":{"date-parts":[[2017,11,12]],"date-time":"2017-11-12T21:58:37Z","timestamp":1510523917000},"page":"1978-1987","source":"Crossref","is-referenced-by-count":10,"title":["Mechanistic Insights on Human Phosphoglucomutase Revealed by Transition Path Sampling and Molecular Dynamics Calculations"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3130-9807","authenticated-orcid":false,"given":"Nat\u00e9rcia F.","family":"Br\u00e1s","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre, s\/n 4169-007 Porto Portugal"},{"name":"Department of Chemistry and Biochemistry University of Arizona  1306 East University Boulevard Tucson Arizona 85721 USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-4722","authenticated-orcid":false,"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"UCIBIO, REQUIMTE, Departamento de Qu\u00edmica e Bioqu\u00edmica, Faculdade de Ci\u00eancias Universidade do Porto  Rua do Campo Alegre, s\/n 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  Rua do Campo Alegre, s\/n 4169-007 Porto Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0308-1059","authenticated-orcid":false,"given":"Steven D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of 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