《Nature》杂志上发表美国贝勒医学院的Zhou Ming 研究员的新论文，研究通过X射线晶体学技术，揭示出了一种哺乳动物硬脂酰辅酶A去饱和酶(SCD)的结构。
SCD是一种内质网酶，是合成单不饱和脂肪酸的限速酶，SCD对于脂肪酸代谢至关重要。SCD1是一种定位在内质网的跨膜整合蛋白，它可以催化硬脂酰辅酶A和棕榈酰辅酶A第9和10碳原子间形成一个Cis双键。Cis双键的引入是由一组微粒体的电子传递蛋白所介导，包括NADH-细胞色素b5还原酶，细胞色素b5和传递链末端的SCD-1;在NADH的存在下，氧化型细胞色素b5经细胞色素b5还原酶催化转化为还原型细胞色素b5，伴随着电子的传递，O2被还原成H2O，而饱和脂肪酸在SCD的催化下转化为单不饱和脂肪酸。
为了更好地了解SCD功能特征的结构基础，在这篇Nature文章中研究人员解析了与硬脂酰辅酶A结合的小鼠SCD1的晶体结构，分辨率达到2.6埃。这一结构揭示出了由4个跨膜螺旋构成的一个新蛋白质折叠，顶端有一个胞质结构域，以及底物横向进入和产物出去的一条通道。结合硬脂酰辅酶A的酰基链进入到了胞质结构域的一个通道(tunnel)中，这一通道的几何结构及结合酰基链的构象揭示出了脱饱和反应区域选择性和立体定向性的结构基础。9个保守的组氨酸残基呈独特空间排布协调了双铁中心，表明了氧激活的一种潜在新机制。这一结果也显示了电子从细胞色素b5传递至双铁中心的一条可能的路径。
原文链接：
X-ray structure of a mammalian stearoyl-CoA desaturase
原文摘要：
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 regioselecivity 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.
