4.C.3 The Acyl-CoA Thioesterase (ACoT) Family

Peroxisomes metabolize a variety of lipids, acting as a chain-shortening system that produces acyl-CoAs of varying chain lengths, including acetyl-CoA and propionyl-CoA. Peroxisomes contain carnitine acetyltransferase (CRAT) and carnitine octanoyltransferase (CROT) that produce carnitine esters for transport out of peroxisomes, together with recently characterized acyl-CoA thioesterases (ACOTs) that produce free fatty acids. Westin et al. (2008) performed tissue expression profiling of the short- and medium-chain carnitine acyltransferases Crat, Crot and the short- and medium-chain thioesterases (Acot12) and (Acot5). They provided evidence that these enzymes are largely expressed in different tissues and do not compete for the same substrates. Rather, they provide complementary systems for transport of metabolites across the peroxisomal membrane. This may explain earlier observed tissue differences in peroxisomal production of acetyl-CoA/acetyl-carnitine/acetate and underscores the differences in peroxisome function in various organs.

Peroxisomes perform β-oxidation of a variety of long chain aliphatic, branched, and aromatic carboxylic acids. Import of substrates into peroxisomes for β-oxidation is mediated by ATP binding cassette (ABC) transporter proteins of subfamily D, which includes the human adrenoleukodystropy protein (ALDP TC# 3.A.1.203.3) defective in X-linked adrenoleukodystrophy (X-ALD). Whether substrates are transported as CoA esters or free acids has been a matter of debate. Using COMATOSE (CTS; TC#3.A.1.203.5), a plant representative of the ABCD family.  De Marcos Lousa et al. (2013) demonstrated that there is a functional and physical interaction between the ABC transporter and the peroxisomal long chain acyl-CoA synthetases (LACS)6 and 7.  CTS possess fatty acyl-CoA thioesterase activity which is stimulated by ATP. A mutant, in which Serine 810 is replaced by asparagine (S810N) is defective in fatty acid degradation in vivo, retains ATPase activity but has strongly reduced thioesterase activity, providing evidence for the biological relevance of this activity. Thus, CTS, and most likely the other ABCD family members, represent rare examples of polytopic membrane proteins with an intrinsic additional enzymatic function that may regulate the entry of substrates into the β-oxidation pathway. The cleavage of CoA raises questions about the side of the membrane where this occurs.  

Acyl protein thioesterase hydrolyzes fatty acids from S-acylated cysteine residues in proteins (Lin and Conibear 2015), and has depalmitoylating activity towards a variety of acylated proteins. S-Acylation, the reversible post-translational lipid modification of proteins, is important for control of the properties and functions of ion channels and other polytopic transmembrane proteins, suggeesting that at least some members of this family could be classified into TC subclass 8.A. McClafferty et al., 2020 (PMID 33453888) showed that ABHD17a (alpha/beta-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels, inhibiting channel activity independently of effects on channel surface expression. ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0-S1 domains conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases, revealing mechanisms for generating both specificity and diversity for these  enzymes to control the properties and functions of ion channels (McClafferty et al., 2020 (PMID 33453888)).

The reaction catalyzed by Acyl-CoA thioesterase (thioester hydrolase) is:

Acyl-CoA   →   Fatty Acid    Coenzyme A

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