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Despite extensive research, the molecular details of the FAS catalytic mechanisms are still poorly understood. For example, the \u03b2\u2010ketoacyl synthase (KS) catalyzes the fatty acid elongating carbon\u2010carbon\u2010bond formation, which is the key catalytic step in biosynthesis, but factors that determine the speed and accuracy of his reaction are still unclear. Here, we report enzyme kinetics of the KS\u2010mediated carbon\u2010carbon bond formation, enabled by a continuous fluorometric activity assay. We observe that the KS is likely rate\u2010limiting to the fatty acid biosynthesis, its kinetics are adapted to the length of the bound fatty acyl chain, and that the KS is also responsible for the fidelity of biosynthesis by preventing intermediates from undergoing KS\u2010mediated elongation. To provide mechanistic insight into KS selectivity, we performed computational molecular dynamics (MD) simulations. We identify positive cooperativity of the KS dimer, which we suggest to affect the conformational variability of the multienzyme. Advancing our knowledge about the KS molecular mechanism will pave the ground for engineering FAS for biotechnology applications and the design of new therapeutics targeting the fatty acid metabolism.<\/jats:p>","DOI":"10.1002\/anie.202412195","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T10:03:36Z","timestamp":1731319416000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Kinetics of Carbon\u2010Carbon Bond Formation in Metazoan Fatty Acid Synthase and Its Impact on Product Fidelity"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9159-0271","authenticated-orcid":false,"given":"Christian","family":"Gusenda","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Chemical Biology Buchmann Institute of Molecular Life Sciences Goethe University Frankfurt  Max-von-Laue-Str. 15 60438 Frankfurt am Main Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1123-0413","authenticated-orcid":false,"given":"Ana R.","family":"Calixto","sequence":"additional","affiliation":[{"name":"LAQV, 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":"Joana R.","family":"Da Silva","sequence":"additional","affiliation":[{"name":"LAQV, 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\/0000-0003-2748-4722","authenticated-orcid":false,"given":"Pedro A.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"LAQV, 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\/0000-0002-7269-0667","authenticated-orcid":false,"given":"Martin","family":"Grininger","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Chemical Biology Buchmann Institute of Molecular Life Sciences Goethe University Frankfurt  Max-von-Laue-Str. 15 60438 Frankfurt am Main Germany"}]}],"member":"311","published-online":{"date-parts":[[2024,12,4]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1177\/0148607115595980"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2330"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1161269"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.1c00147"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.02.021"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25173935"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2006.00608.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","unstructured":"S.\u2005J. 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