Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Lipid Res. 2012 Dec;53(12):2620-31. doi: 10.1194/jlr.M029538. Epub 2012 Sep 19.
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.
硫酯酶超家族成员 1（Them1；同义词酰基辅酶 A 硫酯酶 11 和 StarD14）在棕色脂肪组织中高度表达，并限制小鼠的能量消耗。Them1 是一种假定的脂肪酸酰基辅酶 A 硫酯酶，由串联热狗折叠硫酯酶结构域和一个脂质结合甾体急性调节蛋白相关脂质转移（START）结构域组成。为了更好地定义其在代谢调节中的作用，本研究检查了 Them1 的生化和酶学特性。纯化的重组 Them1 在溶液中二聚化形成活性脂肪酸酰基辅酶 A 硫酯酶。二聚化由脂肪酸酰基辅酶 A、辅酶 A（CoASH）、ATP 和 ADP 诱导。Them1 水解一系列脂肪酸酰基辅酶 A，但对长链分子种类表现出相对偏好。硫酯酶活性随温度变化呈负相关，受 ATP 刺激，受 ADP 和 CoASH 抑制。虽然 Them1 的硫酯酶结构域足以产生活性重组蛋白，但 START 结构域是最佳酶活性所必需的。对来自小鼠棕色脂肪组织和肝脏的亚细胞级分的分析表明，Them1 主要贡献于微粒体和核的脂肪酸酰基辅酶 A 硫酯酶活性。这些发现表明，在生理条件下，Them1 作为一种受脂质调节的脂肪酸酰基辅酶 A 硫酯酶发挥作用，可作为代谢紊乱管理的靶标。
