Structural enzymology of cholesterol biosynthesis and storage.

Tao Long, Erik W Debler, Xiaochun Li

Journal: Current opinion in structural biology 2022;74():102369

PMID: 35398802

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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.

Address: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: [email protected].; Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Electronic address: [email protected].

DOI: 10.1016/j.sbi.2022.102369

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MeSH Terms: 3-Hydroxysteroid Dehydrogenases, Cholesterol, Endoplasmic Reticulum, Humans, Lipid Metabolism, Sterol O-Acyltransferase, Water