Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Because 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 homologues (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 catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b5, which regenerates the di-iron centre. To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve 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 the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre.

中文翻译：

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哺乳动物硬脂酰辅酶 A 去饱和酶的 X 射线结构

硬脂酰辅酶A去饱和酶（SCD）在所有真核生物中都是保守的，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 在脂肪酸代谢中起着关键作用。人类有两个 SCD 同源物（SCD1 和 SCD5），而小鼠有四个（SCD1–SCD4）。由于脂质代谢谱和胰岛素敏感性得到改善，SCD1 缺陷小鼠在喂食高脂肪饮食时不会变得肥胖或糖尿病。因此，SCD1 是治疗肥胖症、糖尿病和其他代谢疾病的药理学靶点。SCD1 是位于内质网中的完整膜蛋白，催化硬脂酰辅酶 A 或棕榈酰辅酶 A 的第 9 个和第 10 个碳原子之间形成顺式双键。该反应需要由双铁中心激活的分子氧和再生双铁中心的细胞色素 b5。为了更好地理解 SCD 功能的这些特征的结构基础，我们在这里以 2.6 Å 的分辨率结晶并解析与硬脂酰辅酶 A 结合的小鼠 SCD1 的结构。该结构显示了一个新的折叠，包括四个由胞质结构域覆盖的跨膜螺旋，以及一个用于横向底物进入和产品出口的合理途径。结合的硬脂酰辅酶 A 的酰基链被封闭在一个埋在胞质域中的隧道中，隧道的几何形状和结合的酰基链的构象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。双金属中心由九个保守组氨酸残基的独特空间排列协调，这意味着氧活化的潜在新机制。该结构还说明了电子从细胞色素 b5 转移到双铁中心的可能途径。