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A Combined Quantum Mechanics\/ Molecular Mechanics (QM\/MM) and Molecular Dynamics (MD) study on the catalytic mechanism of KDM6A\/B reveals that the transition state for the rate\u2010limiting hydrogen atom transfer (HAT) reaction in KDM6A catalysis is stabilized by polar (Asn217) and aromatic (Trp369)\/non\u2010polar (Pro274) residues in contrast to KDM4, KDM6B and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved. KDM6A employs both \u03c3\u2010 and \u03c0\u2010electron transfer pathways for HAT, whereas KDM6B employs the \u03c3\u2010electron pathway. Differences in hydrogen bonding of the Fe\u2010chelating Glu252(KDM6B) contribute to the lower energy barriers in KDM6B vs. KDM6A. The study reveals a dependence of the activation barrier of the rebound hydroxylation on the Fe\u2212O\u2212C angle in the transition state of KDM6A. Anti\u2010correlation of the Zn\u2010binding domain with the active site residues is a key factor distinguishing KDM6A\/B from KDM7\/4s. The results reveal the importance of communication between the Fe center, second coordination sphere, and long\u2010range interactions in catalysis by KDMs and, by implication, other 2OG oxygenases.<\/jats:p>","DOI":"10.1002\/chem.202301305","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T22:27:15Z","timestamp":1685572035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Catalysis by KDM6 Histone Demethylases \u2013 A Synergy between the Non\u2010Heme Iron(II) Center, Second Coordination Sphere, and Long\u2010Range Interactions"],"prefix":"10.1002","volume":"29","author":[{"given":"Simahudeen Bathir Jaber Sathik","family":"Rifayee","sequence":"first","affiliation":[{"name":"Department of Chemistry Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shobhit S.","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cait","family":"Warner","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Wildey","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"White","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Schofield","sequence":"additional","affiliation":[{"name":"Chemistry Research laboratory Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford  Oxford OX1 3TA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4481-0246","authenticated-orcid":false,"given":"Christo Z.","family":"Christov","sequence":"additional","affiliation":[{"name":"Department of Chemistry Michigan Technological University  Houghton MI-49931 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2010.08.011"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01080"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.082249499"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.009"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-044724"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.22643"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.246561.114"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201607032"},{"key":"e_1_2_9_9_1","first-page":"1","volume":"6","author":"Labb\u00e9 R. 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