Abstract
Peroxisomes are organelles that function in the beta-oxidation of long- and very 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, that hydrolyze acyl-CoAs to the free fatty acid and coenzyme A. PTE-Ia and PTE-Ic show 82% sequence identity at the amino acid level, and a putative peroxisomal type 1 targeting signal of -AKL was identified at the carboxyl-terminal end of both proteins. Localization experiments using green fluorescent fusion protein showed PTE-Ia 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, whereas 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 intraperoxisomal levels of acyl-CoA, and they may have a function in termination of beta-oxidation of fatty acids of different chain lengths. Tissue expression studies revealed that PTE-Ia is highly expressed in kidney, whereas PTE-Ic is most highly expressed in spleen, brain, testis, and proximal and distal intestine. Both PTE-Ia and PTE-Ic were highly up-regulated in mouse liver by treatment with the peroxisome proliferator WY-14,643 and by fasting in a peroxisome proliferator-activated receptor alpha-dependent manner. These data show that PTE-Ia and PTE-Ic have different functions based on different substrate specificities and tissue expression.
Highlights
PTE-Ic is most highly expressed in spleen, brain, testis, and proximal and distal intestine
Lack of regulation of enzyme activity by free CoASH suggests that PTE-Ia and PTE-Ic regulate intrachain CoA esters results in chain shortening of fatty acids, which may be transported to the mitochondria as carnitine esters for further oxidation. -Oxidation of other types of lipids such as prostanoids leads to chain shortening in the peroxisome for excretion as free carboxylic acids in the urine [3]
These effects are mediated via the peroxisome proliferator-activated receptor alpha (PPAR␣),1 which was shown to be a nuclear receptor in control peroxisomal levels of acyl-CoA, and they may have a of lipid metabolism [5, 6]
Summary
PPAR␣, peroxisome proliferator-activated receptor ␣; CoASH, coenzyme A; PTE, peroxisomal acyl-CoA thioesterase; GFP, green fluorescent protein; EST, expressed sequence. Another peroxisomal acyl-CoA thioesterase called PTE-2, which is unrelated to the Type-I gene family above, was identified as the major acyl-CoA thioesterase in mouse liver peroxisomes [19], with homologues in human, yeast, and plants (20 –23) This is a broad range acyl-CoA thioesterase that hydrolyzes almost all acyl-CoAs present in peroxisomes, including bile acid-CoA esters, short-, medium-, and long-chain acyl-CoAs and intermediates from -oxidation of pristanoyl-CoA. We have cloned and characterized PTE-Ia and PTE-Ic, the latter of which is a newly identified member of the Type-I family of acyl-CoA thioesterases Both these enzymes are peroxisomal, are highly homologous (Ͼ80% sequence identity at amino acid level), and hydrolyze long- and mediumchain acyl-CoAs, respectively. These enzymes may play a role in controlling acyl-CoA levels within the peroxisome in different tissues
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