Contreras J A, Karlsson M, Osterlund T, Laurell H, Svensson A, Holm C
Department of Cell and Molecular Biology, Lund University, Lund S-221 00, Sweden.
J Biol Chem. 1996 Dec 6;271(49):31426-30. doi: 10.1074/jbc.271.49.31426.
Hormone-sensitive lipase is the key enzyme in the mobilization of fatty acids from adipose tissue, thereby playing a crucial role in the overall energy homeostasis in mammals. Its activity is stimulated by catecholamines through cAMP-dependent phosphorylation of a single serine, a process that is prevented by insulin. This regulatory property is unique to this enzyme among all known lipases and has been acquired during evolution through insertion of a regulatory module into an ancestral lipase. Sequence alignments have failed to detect significant homology between hormone-sensitive lipase and the rest of the mammalian lipases and esterases, to which this enzyme is only very distantly related. In the present work, we report the finding of a remarkable secondary structure homology between hormone-sensitive lipase and the enzymes from a superfamily of esterases and lipases that includes acetylcholinesterase, bile salt-stimulated lipase, and several fungal lipases. This finding, based on the identification of the secondary structure elements in the hormone-sensitive lipase sequence, has allowed us to construct a three-dimensional model for the catalytic domain of hormone-sensitive lipase. The model reveals the topological organization, predicts the components of the catalytic triad, suggests a three-dimensional localization of the regulatory module, and provides a valuable tool for the future study of structural and functional aspects of this metabolically important enzyme.
激素敏感脂肪酶是从脂肪组织中动员脂肪酸的关键酶，因此在哺乳动物的整体能量稳态中起着至关重要的作用。其活性通过儿茶酚胺对单个丝氨酸的cAMP依赖性磷酸化而被刺激，这一过程会被胰岛素阻止。在所有已知的脂肪酶中，这种调节特性是该酶所独有的，并且是在进化过程中通过将一个调节模块插入到一个祖先脂肪酶中而获得的。序列比对未能检测到激素敏感脂肪酶与其他哺乳动物脂肪酶和酯酶之间的显著同源性，该酶与它们的关系非常疏远。在本研究中，我们报告了在激素敏感脂肪酶与一个酯酶和脂肪酶超家族的酶之间发现了显著的二级结构同源性，该超家族包括乙酰胆碱酯酶、胆汁盐刺激脂肪酶和几种真菌脂肪酶。基于对激素敏感脂肪酶序列中二级结构元件的鉴定，这一发现使我们能够构建激素敏感脂肪酶催化结构域的三维模型。该模型揭示了拓扑结构组织，预测了催化三联体的组成成分，暗示了调节模块的三维定位，并为未来研究这种在代谢方面重要的酶的结构和功能方面提供了一个有价值的工具。
