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We have recently found that the cytosolic enzyme ECHDC1 degrades ethylmalonyl-CoA and methylmalonyl-CoA, which presumably result from promiscuous reactions catalyzed by acetyl-CoA carboxylase on butyryl- and propionyl-CoA. Here, we tested the hypothesis that ECHDC1 is a metabolite repair enzyme that serves to prevent the formation of methyl- or ethyl-branched FAs by FASN. Using the purified enzyme, we found that FASN can incorporate not only methylmalonyl-CoA but also ethylmalonyl-CoA, producing methyl- or ethyl-branched FAs. Using a combination of gas-chromatography and liquid chromatography coupled to mass spectrometry, we observed that inactivation of ECHDC1 in adipocytes led to an increase in several methyl-branched FAs (present in different lipid classes), while its overexpression reduced them below wild-type levels. In contrast, the formation of ethyl-branched FAs was observed almost exclusively in ECHDC1 knockout cells, indicating that ECHDC1 and the low activity of FASN toward ethylmalonyl-CoA efficiently prevent their formation. We conclude that ECHDC1 performs a typical metabolite repair function by destroying methyl- and ethylmalonyl-CoA. This reduces the formation of methyl-branched FAs and prevents the formation of ethyl-branched FAs by FASN. The identification of ECHDC1 as a key modulator of the abundance of methyl-branched FAs opens the way to investigate their function.<\/jats:p>","DOI":"10.1042\/bcj20190500","type":"journal-article","created":{"date-parts":[[2019,8,15]],"date-time":"2019-08-15T12:05:11Z","timestamp":1565870711000},"page":"2427-2447","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA"],"prefix":"10.1042","volume":"476","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7223-2706","authenticated-orcid":false,"given":"Joseph P.","family":"Dewulf","sequence":"first","affiliation":[{"name":"Laboratory of Physiological Chemistry, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Brussels B-1200, Belgium"},{"name":"Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Gerin","sequence":"additional","affiliation":[{"name":"Laboratory of Physiological Chemistry, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark H.","family":"Rider","sequence":"additional","affiliation":[{"name":"PHOS Laboratory, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Veiga-da-Cunha","sequence":"additional","affiliation":[{"name":"Laboratory of Physiological Chemistry, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile","family":"Van Schaftingen","sequence":"additional","affiliation":[{"name":"Laboratory of Physiological Chemistry, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6898-4884","authenticated-orcid":false,"given":"Guido T.","family":"Bommer","sequence":"additional","affiliation":[{"name":"Laboratory of Physiological Chemistry, de Duve Institute, UCLouvain, Brussels B-1200, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2019,8,30]]},"reference":[{"key":"2021112218001865900_BCJ-2019-0500C1","first-page":"669","article-title":"Fatty acid synthesis in adipose tissue. 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