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Despite their desirability, efficient design and production of these compounds has not been achieved to date. The catalytic mechanism of patellamide macrocyclization by the PatG macrocyclase domain has been computationally investigated by using quantum mechanics\/molecular mechanics methodology, specifically ONIOM(M06\/6\u2010311++G(2d,2p):ff94\/\/B3LYP\/6\u201031G(d):ff94). The mechanism proposed herein begins with a proton transfer from Ser783 to His 618 and from the latter to Asp548. Nucleophilic attack of Ser783 on the substrate leads to the formation of an acyl\u2013enzyme covalent complex. The leaving group Ala\u2010Tyr\u2010Asp\u2010Gly (AYDG) of the substrate is protonated by the substrate's N\u2005terminus, leading to the breakage of the P1\u2212P1\u2032 bond. Finally, the substrate's N\u2005terminus attacks the P1 residue, decomposing the acyl\u2013enzyme complex forming the macrocycle. The formation and decomposition of the acyl\u2013enzyme complex have the highest activation free energies (21.1\u2005kcal\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    and 19.8\u2005kcal\u2009mol\n                    <jats:sup>\u22121<\/jats:sup>\n                    respectively), typical of serine proteases. Understanding the mechanism behind the macrocyclization of patellamides will be important to the application of the enzymes in the pharmaceutical and biotechnological industries.\n                  <\/jats:p>","DOI":"10.1002\/chem.201601670","type":"journal-article","created":{"date-parts":[[2016,7,8]],"date-time":"2016-07-08T06:28:04Z","timestamp":1467959284000},"page":"13089-13097","source":"Crossref","is-referenced-by-count":17,"title":["The Catalytic Mechanism of the Marine\u2010Derived Macrocyclase PatGmac"],"prefix":"10.1002","volume":"22","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"}]},{"given":"Pedro","family":"Ferreira","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"}]},{"given":"Ana R.","family":"Calixto","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"}]},{"given":"Marcel","family":"Jaspars","sequence":"additional","affiliation":[{"name":"Marine Biodiscovery Centre Department of Chemistry University of Aberdeen  Old Aberdeen AB24 3UE, Scotland UK"}]},{"given":"Wael","family":"Houssen","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences University of Aberdeen  Aberdeen AB25 2ZD, Scotland UK"},{"name":"Pharmacognosy Department Faculty of Pharmacy Mansoura University  Mansoura 35516 Egypt"}]},{"given":"James H.","family":"Naismith","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research Complex University of St Andrews  North Haugh St Andrews, Fife KY16 9ST, Scotland UK"}]},{"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"}]},{"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"}]}],"member":"311","published-online":{"date-parts":[[2016,7,8]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"C&EN Supplement on \u201cThe top 50 drugs of 2014\u201d September 2014."},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1584"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm400887j"},{"key":"e_1_2_6_4_1","unstructured":"\u00a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2590"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1062"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/C2NP20085F"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1039\/c1cc13322e"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1586"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.10.015"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2340"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja1067806"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201000230"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1626"},{"key":"e_1_2_6_15_1","unstructured":"T.\u2005R.\u2005K. 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