X-ray structure of a mammalian stearoyl-CoA desaturase.
X-ray structure of a mammalian stearoyl-CoA desaturase.
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DOI：
10.1038/nature14549
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发表时间：
2015-08-13
期刊：
影响因子：
64.8
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Bai Y;McCoy JG;Levin EJ;Sobrado P;Rajashankar KR;Fox BG;Zhou M
硬脂酰辅酶A去饱和酶（SCD）在所有真核生物中是保守的，并将第一个双键引入饱和脂肪酰辅酶A中。由于SCD的单不饱和产物是膜磷脂、胆固醇酯和甘油三酯的关键前体，因此SCD在脂肪酸代谢中是关键的。人类有两个SCD同源物（SCD 1和SCD 5），而小鼠有四个（SCD 1-SCD 4）。SCD 1缺陷小鼠在喂食高脂肪饮食时不会变得肥胖或糖尿病，因为脂质代谢谱和胰岛素敏感性得到改善。因此，SCD 1是治疗肥胖症、糖尿病和其他代谢疾病的药理学靶标。SCD 1是位于内质网中的一种整合膜蛋白，催化硬脂酰或棕榈酰CoA的第9和第10个碳之间的顺式双键的形成。该反应需要分子氧和细胞色素b5，分子氧被二铁中心激活，细胞色素b5再生二铁中心。为了更好地理解SCD功能的这些特征的结构基础，我们在2.6 nm分辨率下结晶并解析了与硬脂酰辅酶A结合的小鼠SCD 1的结构。该结构显示了一种新的折叠，包括由胞质结构域封端的四个跨膜螺旋，以及侧向底物进入和产物流出的合理途径。结合的硬脂酰辅酶A的酰基链被封闭在胞质结构域中的隧道中，并且隧道的几何形状和结合的酰基链的构型为去饱和反应的区域选择性和立体特异性提供了结构基础。双金属中心是协调的9个保守的组氨酸残基，这意味着一个潜在的新的金属中心和氧活化机制的独特配置。该结构还说明了一个可能的途径，从细胞色素b5的二铁中心的电子转移。
Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Since the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters, and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologs (SCD1 and SCD5), while mice have four (SCD1–SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity. Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes, and other metabolic diseases. SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyzes the formation of a cis-double bond between the 9th and 10th carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a diiron center, and cytochrome b5, which regenerates the diiron center. To better understand the structural basis of these characteristics of SCD function, we crystallized and solved the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 Å resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and configuration of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal center is coordinated by a unique configuration of nine conserved histidine residues that implies a potentially novel metal center and mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the diiron center.