{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T18:03:40Z","timestamp":1760551420181,"version":"3.37.3"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"Supplement_1","license":[{"start":{"date-parts":[[2021,7,12]],"date-time":"2021-07-12T00:00:00Z","timestamp":1626048000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF19OC0057834"],"award-info":[{"award-number":["NNF19OC0057834"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004836","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["DFF-0135-00420B","DFF-7014-00041"],"award-info":[{"award-number":["DFF-0135-00420B","DFF-7014-00041"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>The design of enzymes is as challenging as it is consequential for making chemical synthesis in medical and industrial applications more efficient, cost-effective and environmentally friendly. While several aspects of this complex problem are computationally assisted, the drafting of catalytic mechanisms, i.e. the specification of the chemical steps\u2014and hence intermediate states\u2014that the enzyme is meant to implement, is largely left to human expertise. The ability to capture specific chemistries of multistep catalysis in a fashion that enables its computational construction and design is therefore highly desirable and would equally impact the elucidation of existing enzymatic reactions whose mechanisms are unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We use the mathematical framework of graph transformation to express the distinction between rules and reactions in chemistry. We derive about 1000 rules for amino acid side chain chemistry from the M-CSA database, a curated repository of enzymatic mechanisms. Using graph transformation, we are able to propose hundreds of hypothetical catalytic mechanisms for a large number of unrelated reactions in the Rhea database. We analyze these mechanisms to find that they combine in chemically sound fashion individual steps from a variety of known multistep mechanisms, showing that plausible novel mechanisms for catalysis can be constructed computationally.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The source code of the initial prototype of our approach is available at https:\/\/github.com\/Nojgaard\/mechsearch<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btab296","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T20:46:37Z","timestamp":1619469997000},"page":"i392-i400","source":"Crossref","is-referenced-by-count":6,"title":["Graph transformation for enzymatic mechanisms"],"prefix":"10.1093","volume":"37","author":[{"given":"Jakob L","family":"Andersen","sequence":"first","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]},{"given":"Rolf","family":"Fagerberg","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]},{"given":"Christoph","family":"Flamm","sequence":"additional","affiliation":[{"name":"Department of Theoretical Chemistry, University of Vienna , Vienna,","place":["Austria"]}]},{"given":"Walter","family":"Fontana","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Harvard Medical School , Boston, MA,","place":["USA"]}]},{"given":"Juri","family":"Kol\u010d\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]},{"given":"Christophe V F P","family":"Laurent","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]},{"given":"Daniel","family":"Merkle","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]},{"given":"Nikolai","family":"N\u00f8jgaard","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Southern Denmark , Odense,","place":["Denmark"]}]}],"member":"286","published-online":{"date-parts":[[2021,7,12]]},"reference":[{"key":"2024111106010382600_btab296-B1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1759-2208-4-4","article-title":"Inferring chemical reaction patterns using rule composition in graph grammars","volume":"4","author":"Andersen","year":"2013","journal-title":"J. Syst. Chem"},{"key":"2024111106010382600_btab296-B2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1504\/IJCBDD.2014.061649","article-title":"Generic strategies for chemical space exploration","volume":"7","author":"Andersen","year":"2014","journal-title":"Int. J. Comput. Biol. Drug Des"},{"key":"2024111106010382600_btab296-B3","first-page":"73","volume-title":"Graph Transformation. ICGT 2016. Lecture Notes in Computer Science","author":"Andersen","year":"2016"},{"key":"2024111106010382600_btab296-B4","first-page":"54","volume-title":"Graph Transformation. ICGT 2017. Lecture Notes in Computer Science","author":"Andersen","year":"2017"},{"key":"2024111106010382600_btab296-B5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/wcms.61","article-title":"Computer-aided synthesis design: 40 years on","volume":"2","author":"Cook","year":"2012","journal-title":"WIREs Comput. Mol. 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