ECHDC1, also known as ethylmalonyl-CoA decarboxylase, is a cytosolic enzyme that decarboxylates ethyl-or methyl-malonyl-CoA, side products of acetyl-CoA carboxylase. It is involved in the metabolism of branched-chain fatty acids (FAs), preventing the formation of abnormal FAs synthesized from these CoA derivatives [1,3,4].

In ECHDC1 knockout mice, ethyl-branched FAs accumulated in all tissues and were incorporated into various lipids. These mice also excreted unusual glycine-conjugates in the urine, which were adducts of ethyl-branched compounds in different oxidation stages. This suggests that the excretion of potentially toxic intermediates of branched-chain FA metabolism may prevent a more severe phenotype. Additionally, 2,2-dimethylmalonyl-CoA accumulated in these knockout mice, indicating that ECHDC1 helps eliminate various potentially dangerous branched-chain dicarboxylyl-CoAs [1].

In conclusion, ECHDC1 plays a crucial role in preventing the formation of ethyl-branched FAs. Studies on ECHDC1 knockout mice have provided insights into the role of ECHDC1 in branched-chain FA metabolism and the body's mechanism of dealing with potentially harmful metabolic intermediates. Although a direct link between ECHDC1 deficiency and disease has not been fully proven, it may be involved in conditions related to abnormal branched-chain FA metabolism, such as in the context of ethylmalonic aciduria where its variants were found to potentially interact with ACADS variants [1,2].

References:

1. Dewulf, Joseph P, Paquay, Stéphanie, Marbaix, Etienne, Van Schaftingen, Emile, Bommer, Guido T. 2021. ECHDC1 knockout mice accumulate ethyl-branched lipids and excrete abnormal intermediates of branched-chain fatty acid metabolism. In The Journal of biological chemistry, 297, 101083. doi:10.1016/j.jbc.2021.101083. https://pubmed.ncbi.nlm.nih.gov/34419447/

2. Fogh, Sarah, Dipace, Graziana, Bie, Anne, Van Schaftingen, Emile, Olsen, Rikke K J. 2021. Variants in the ethylmalonyl-CoA decarboxylase (ECHDC1) gene: a novel player in ethylmalonic aciduria? In Journal of inherited metabolic disease, 44, 1215-1225. doi:10.1002/jimd.12394. https://pubmed.ncbi.nlm.nih.gov/33973257/

3. Dewulf, Joseph P, Gerin, Isabelle, Rider, Mark H, Van Schaftingen, Emile, Bommer, Guido T. 2019. The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. In The Biochemical journal, 476, 2427-2447. doi:10.1042/BCJ20190500. https://pubmed.ncbi.nlm.nih.gov/31416829/

4. Linster, Carole L, Noël, Gaëtane, Stroobant, Vincent, Veiga-da-Cunha, Maria, Van Schaftingen, Emile. 2011. Ethylmalonyl-CoA decarboxylase, a new enzyme involved in metabolite proofreading. In The Journal of biological chemistry, 286, 42992-3003. doi:10.1074/jbc.M111.281527. https://pubmed.ncbi.nlm.nih.gov/22016388/