Ethylmalonyl-CoA decarboxylase (ECHDC1) prevents the synthesis of methyl- and ethyl-branched fatty acids

Abstract

The purpose of the present thesis was to evaluate the function of ECHDC1, a cytosolic enzyme that decarboxylates ethylmalonyl-CoA (em-CoA) and to a lesser extent, methylmalonyl-CoA (mm-CoA). As reviewed in the Introduction, fatty acid synthase (FASN), a cytosolic enzyme, usually elongates acetyl-CoA by successive additions of malonyl-CoA to synthesize straight chain fatty acids (FAs). Less frequently, methyl-branched FAs can be synthesized by starting with CoA esters derived from branched-chain amino acids (replacing acetyl-CoA and forming iso and anteiso FAs), or by using mm-CoA instead of malonyl-CoA during the elongation. Cytosolic mmCoA is formed by a side-reaction of acetyl-CoA carboxylase (ACC) on propionyl-CoA. ACC also acts on butyryl-CoA, thereby forming em-CoA. Incorporation of em-CoA by FASN should lead to the formation of ethyl-branched FAs, but this formation has never been demonstrated. Our working hypothesis on the function of ECHDC1 was that by destroying the two side products of ACC, it would prevent the formation of branched-FAs. We first showed in the Results section that mammalian FASN is not only able to synthesize straight or methyl-branched FAs, but also ethyl-branched FAs. Yet, the catalytic activity observed with emCoA is very weak compared to those observed with malonyl-CoA and mm-CoA. Metabolomic analysis of ECHDC1 KO adipocytes revealed a several-fold increase in the amount of methyl-branched FAs, derived from propionate as shown by isotopic labeling. Feeding the KO cells with labeled ethylmalonate led to the formation of ethyl-branched FAs. Analysis of ECHDC1 KO mice confirmed an increase in the formation of methyl-branched FAs. Yet, the most striking observation was that this deficiency led to the appearance of ethyl-branched FAs in tissues. We also discovered a remarkable accumulation of medium chain ethyl-branched FAs. These species were found in liver mitochondria as CoA esters and were excreted in urine mainly as glycine and taurine conjugates in various states of oxidation. Stable isotope labeling experiments indicated that they were probably ethyl-branched. These findings highlight that, contrary to methyl-branched FAs, mammals are not able to metabolize ethyl-branched FAs. Metabolism owns an elegant double control to prevent their formation, (1) the FASN activity towards em-CoA is very weak and (2) ECHDC1 decarboxylates em-CoA, preventing its incorporation by FASN.(MED - Sciences médicales) -- UCL, 201