Acyl-CoA thioesterases : auxiliary enzymes in peroxisomal lipid metabolism

Peroxisomes are small organelles essential for life, which carry out a variety of functions mostly related to lipid metabolism, including α- and β-oxidation as well as the first steps of plasmalogen biosynthesis. Peroxisomal β-oxidation metabolizes many different lipids including very long-chain fatty acids, dicarboxylic fatty acids, branched-chain fatty acids, eicosanoids and certain xenobiotic fatty acids.

This PhD project began with the identification of four novel putative peroxisomal acyl- CoA thioesterase genes, named acyl-CoA thioesterase 3-6 (Acot3-Acot6). The acyl- CoA thioesterases are a group of enzymes that catalyze the hydrolysis of acyl-CoAs to free fatty acids and coenzyme A. The identification of these novel acyl-CoA thioesterases raised questions as to their function(s) and what the need is for so many peroxisomal acyl-CoA thioesterases. Answering these questions was therefore the aim of this project. Biochemical characterization showed that expression of all four enzymes is upregulated by peroxisome proliferators in a peroxisome proliferatoractivated receptor α (PPARα) dependent manner, suggesting that they function in fatty acid metabolism.

Further characterization revealed that ACOT3 and ACOT5 are a long- and a medium-chain acyl-CoA thioesterase, respectively, while ACOT4 and ACOT6 were shown to be specific enzymes catalyzing the hydrolysis of succinyl-CoA and phytanoyl-CoA/pristanoyl-CoA, respectively. ACOT3-ACOT6 were also shown to have distinct tissue expression patterns, suggesting that these enzymes carry out specific functions in different tissues. The peroxisomal acyl-CoA thioesterases not only have the potential to terminate oxidation by hydrolysis of the acyl-CoAs, but the free fatty acids produced may also be able to exit peroxisomes, suggesting a function for these enzymes in transport of fatty acids out of peroxisomes. A wide variety of lipids are oxidized in peroxisomes producing a diversity of products that require to exit peroxisomes, which demonstrates the need for multiple acyl-CoA thioesterase activities in peroxisomal lipid metabolism.

List of scientific papers

I. Westin MA, Alexson SE, Hunt MC (2004). Molecular cloning and characterization of two mouse peroxisome proliferator-activated receptor alpha (PPARalpha)-regulated peroxisomal acyl-CoA thioesterases. J Biol Chem. 279(21): 21841-8. Epub 2004 Mar 8
https://pubmed.ncbi.nlm.nih.gov/15007068

II. Westin MA, Hunt MC, Alexson SE (2005). The identification of a succinyl-CoA thioesterase suggests a novel pathway for succinate production in peroxisomes. J Biol Chem. 280(46): 38125-32. Epub 2005 Aug 31
https://pubmed.ncbi.nlm.nih.gov/16141203

III. Westin MAK, Hunt MC, Alexson SEH (2007). Peroxisomes contain a specfic phytanoyl-CoA/pristanoyl-CoA thioesterase acting as a novel auxiliary enzyme in alpha- and beta-oxidation of methyl-branched fatty acids. [Submitted]

IV. Westin MAK, Hunt MC, Alexson SEH (2007). Tissue expression studies of enzymes involved in peroxisomal lipid metabolism-new insights into the functions of acyl-CoA thioesterases and carnitine acyltransferases. [Submitted]