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Biochemistry and molecular biology
Peroxisomes are organelles that function in the b-oxidation of very-long and long-chain acyl-CoAs, bile acid-CoA intermediates, prostaglandins, leukotrienes, thromboxanes, dicarboxylic fatty acids, pristanic acid and xenobiotic carboxylic acids. The very long- and long-chain acyl-CoAs are mainly chain-shortened and then transported to mitochondria for further metabolism. We have now identified and characterized two peroxisomal acyl- CoA thioesterases, named PTE-Ia and PTE-Ic, which hydrolyze acyl-CoAs to the free fatty acid and coenzyme A. PTE-Ia and PTE-Ic show 82% sequence identity at amino acid level and a putative peroxisomal type 1 targeting signal of –AKL was identified at the carboxy-terminal end of both proteins. Localization experiments using green fluorescent fusion protein showed PTEIa and PTE-Ic to be localized in peroxisomes. Despite their high level of sequence identity, we show that PTE-Ia is mainly active on long-chain acyl- CoAs, while PTE-Ic is mainly active on medium-chain acyl-CoAs. Lack of regulation of enzyme activity by free CoASH suggests that PTE-Ia and PTE-Ic regulate intra-peroxisomal levels of acyl-CoA, and they may have a function in termination of b-oxidation of fatty acids of different chain-lengths. Tissue expression studies revealed that PTE-Ia is highly expressed in kidney, while PTE-Ic is most highly expressed in spleen, brain, testis and proximal and distal intestine. Both PTE-Ia and PTE-Ic were highly upregulated in mouse liver by treatment with the peroxisome proliferator WY-14,643 and by fasting, in a peroxisome proliferator-activated receptor alpha (PPARa) dependent manner. These data show that PTE-Ia and PTE-Ic have different functions based on different substrate specificities and tissue expression.
Westin M. A., Alexson S. E. H. and Hunt M. C. Molecular cloning and characterization of two mouse peroxisome proliferator-activated receptor alpha (PPARa) regulated peroxisomal acyl-CoA thioesterases. J. Biol. Chem. (2004) 279 (21): 21,841-21,848. doi:10.1074/jbc.M313863200