title: Characterization of an acyl-coA thioesterase that functions as a major regulator of peroxisomal lipid metabolism.
abstract: Peroxisomes function in beta-oxidation of very long and long-chain fatty acids, dicarboxylic fatty acids, bile acid intermediates, prostaglandins, leukotrienes, thromboxanes, pristanic acid, and xenobiotic carboxylic acids. These lipids are mainly chain-shortened for excretion as the carboxylic acids or transported to mitochondria for further metabolism. Several of these carboxylic acids are slowly oxidized and may therefore sequester coenzyme A (CoASH). To prevent CoASH sequestration and to facilitate excretion of chain-shortened carboxylic acids, acyl-CoA thioesterases, which catalyze the hydrolysis of acyl-CoAs to the free acid and CoASH, may play important roles. Here we have cloned and characterized a peroxisomal acyl-CoA thioesterase from mouse, named PTE-2 (peroxisomal acyl-CoA thioesterase 2). PTE-2 is ubiquitously expressed and induced at mRNA level by treatment with the peroxisome proliferator WY-14,643 and fasting. Induction seen by these treatments was dependent on the peroxisome proliferator-activated receptor alpha. Recombinant PTE-2 showed a broad chain length specificity with acyl-CoAs from short- and medium-, to long-chain acyl-CoAs, and other substrates including trihydroxycoprostanoyl-CoA, hydroxymethylglutaryl-CoA, and branched chain acyl-CoAs, all of which are present in peroxisomes. Highest activities were found with the CoA esters of primary bile acids choloyl-CoA and chenodeoxycholoyl-CoA as substrates. PTE-2 activity is inhibited by free CoASH, suggesting that intraperoxisomal free CoASH levels regulate the activity of this enzyme. The acyl-CoA specificity of recombinant PTE-2 closely resembles that of purified mouse liver peroxisomes, suggesting that PTE-2 is the major acyl-CoA thioesterase in peroxisomes. Addition of recombinant PTE-2 to incubations containing isolated mouse liver peroxisomes strongly inhibited bile acid-CoA:amino acid N-acyltransferase activity, suggesting that this thioesterase can interfere with CoASH-dependent pathways. We propose that PTE-2 functions as a key regulator of peroxisomal lipid metabolism.
authors.affiliation: Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. mary.hunt@chemlab.hs.sll.se
authors.forename: Mary C
authors.initials: MC
authors.lastname: Hunt
authors.forename: Karianne
authors.initials: K
authors.lastname: Solaas
authors.forename: B Frode
authors.initials: BF
authors.lastname: Kase
authors.forename: Stefan E H
authors.initials: SE
authors.lastname: Alexson
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D003065:Coenzyme A / Q000378:metabolism; D004790:Enzyme Induction; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008969:Molecular Sequence Data; D020025:Peroxisome Proliferators / Q000494:pharmacology; D020675:Peroxisomes / Q000201:enzymology* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014020:Tissue Extracts / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D014020:Tissue Extracts; C006253:pirinixic acid; D013869:Thiolester Hydrolases; C413373:ACOT2 protein, human; D003065:Coenzyme A