胆固醇生物合成和储存的结构酶学。
Structural enzymology of cholesterol biosynthesis and storage.
机构信息
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
出版信息
Curr Opin Struct Biol. 2022 Jun;74:102369. doi: 10.1016/j.sbi.2022.102369. Epub 2022 Apr 7.
Abstract
Cholesterol biosynthesis occurs in the endoplasmic reticulum (ER). Its lego-like construction from water-soluble small metabolites via intermediates of increasing complexity to water-insoluble cholesterol requires numerous distinct enzymes. Dysfunction of the involved enzymes can cause several human inborn defects and diseases. Here, we review recent structures of three key cholesterol biosynthetic enzymes: Squalene epoxidase (SQLE), NAD(P)-dependent steroid dehydrogenase-like (NSDHL), and 3β-hydroxysteroid Δ-Δ isomerase termed EBP. Moreover, we discuss structures of acyl-CoA:cholesterol acyltransferase (ACAT) enzymes, which are responsible for forming cholesteryl esters from cholesterol to maintain cholesterol homeostasis in the ER. The structures of these enzymes reveal their catalytic mechanism and provide a molecular basis to develop drugs for treating diseases linked to their dysregulation.
摘要
胆固醇生物合成发生在内质网（ER）中。其乐高式的构建，从小分子水溶性代谢物通过中间产物的复杂度增加到不溶于水的胆固醇，需要许多不同的酶。涉及的酶功能障碍会导致几种人类先天性缺陷和疾病。在这里，我们回顾了三种关键胆固醇生物合成酶的最新结构：鲨烯环氧化酶（SQLE）、NAD（P）-依赖性甾体脱氢酶样（NSDHL）和 3β-羟甾醇Δ-Δ异构酶，称为 EBP。此外，我们还讨论了酰基辅酶 A：胆固醇酰基转移酶（ACAT）酶的结构，这些酶负责从胆固醇形成胆固醇酯，以维持 ER 中的胆固醇稳态。这些酶的结构揭示了它们的催化机制，并为开发治疗与其失调相关疾病的药物提供了分子基础。
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