Functional characterization of thioesterase superfamily member 1/Acyl-CoA thioesterase 11: implications for metabolic regulation

Shuxin Han,David E Cohen

doi:10.1194/jlr.m029538

Abstract

Thioesterase superfamily member 1 (Them1; synonyms acyl-CoA thioesterase 11 and StarD14) is highly expressed in brown adipose tissue and limits energy expenditure in mice. Them1 is a putative fatty acyl-CoA thioesterase that comprises tandem hot dog-fold thioesterase domains and a lipid-binding C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain. To better define its role in metabolic regulation, this study examined the biochemical and enzymatic properties of Them1. Purified recombinant Them1 dimerized in solution to form an active fatty acyl-CoA thioesterase. Dimerization was induced by fatty acyl-CoAs, coenzyme A (CoASH), ATP, and ADP. Them1 hydrolyzed a range of fatty acyl-CoAs but exhibited a relative preference for long-chain molecular species. Thioesterase activity varied inversely with temperature, was stimulated by ATP, and was inhibited by ADP and CoASH. Whereas the thioesterase domains of Them1 alone were sufficient to yield active recombinant protein, the START domain was required for optimal enzyme activity. An analysis of subcellular fractions from mouse brown adipose tissue and liver revealed that Them1 contributes principally to the fatty acyl-CoA thioesterase activity of microsomes and nuclei. These findings suggest that under biological conditions, Them1 functions as a lipid-regulated fatty acyl-CoA thioesterase that could be targeted for the management of metabolic disorders.

Highlights

Thioesterase superfamily member 1 (Them[1]; synonyms acyl-CoA thioesterase 11 and StarD14) is highly expressed in brown adipose tissue and limits energy expenditure in mice
In earlier studies (7, 8), we demonstrated that the Abbreviations: Acot, acyl-CoA thioesterase; ATP-␥-S, adenosine 5′-[␥-thio]triphosphate; BAT, brown adipose tissue; brown fat-inducible thioesterase (BFIT), brown fatinducible thioesterase; critical micelle concentration (CMC), critical micellar concentration; CoASH, coenzyme A; GST, glutathione S-transferase; PC-TP, phosphatidylcholine transfer protein; START, steroidogenic acute regulatory protein-related lipid transfer, recombinant protein containing the START domain of Them[1]; Them, thioesterase superfamily member; Thio[1], recombinant protein containing N-terminal thioesterase domain of Them[1]; Thio1/2, recombinant protein containing both thioesterase domains of Them[1]
Our results demonstrate that Them[1] forms a homodimer that preferentially hydrolyzes long-chain fatty acyl-CoAs and that the START domain contributes toward optimizing this activity

Summary

Introduction

Thioesterase superfamily member 1 (Them[1]; synonyms acyl-CoA thioesterase 11 and StarD14) is highly expressed in brown adipose tissue and limits energy expenditure in mice. Purified recombinant Them[1] dimerized in solution to form an active fatty acyl-CoA thioesterase. An analysis of subcellular fractions from mouse brown adipose tissue and liver revealed that Them[1] contributes principally to the fatty acyl-CoA thioesterase activity of microsomes and nuclei. These findings suggest that under biological conditions, Them[1] functions as a lipidregulated fatty acyl-CoA thioesterase that could be targeted for the management of metabolic disorders.—Han, S., and D. Members of the acyl-CoA thioesterase (Acot) gene family hydrolyze acyl-CoA molecules Substrates of these enzymes include a variety of coenzyme A (CoASH) thioesters, including fatty acyl- and acetyl-CoAs (1, 2). Recent studies in mice have linked Acots to nutrient metabolism and energy homeostasis (3, 4)

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Conclusion