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From Proteopedia

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This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Introduction

Lanosterol synthase is an important oxidosqualene cyclase enzyme in the cholesterol biosynthesis pathway. It converts 2,3-Oxidosqualene to a protosterol cation and then to . Lanosterol is a crucial four-ringed precursor to cholesterol.

Since lanosterol synthase is involved in cholesterol biosynthesis, there is clinical relevance in using lanosterol synthase inhibitors to develop cholesterol lowering drugs. These drugs could then potentially be used in conjunction with statins.

Function

The enzyme oxidosqualene cyclase carries out the most complex phase of cholesterol synthesis. It takes a lengthy skinny carbon chain, oxidosqualene, and folds it to create a cyclic compound composed of four connected rings.

Cholesterol Biosynthesis

Cholesterol biosynthesis diverges from other biochemical processes using Acetyl-CoA. Acetyl-CoA molecules, containing two carbons each, are condensed to form five-carbon isoprene units. These isoprene units then affix to generate a long 30 carbon molecule called squalene. Squalene will undergo an epoxidation reaction to form 2,3-oxidosqualene, the substrate for lanosterol synthase. Lanosterol continues in a 19-step pathway to become cholesterol.

Mechanism

Mutagenic analysis has determined that there are three residues vital to protein function: .^[3] The opening of the epoxide ring of 2,3-oxidosqualene requires protonation by the enzyme. The proton donor is the aspartic acid residue D455. Conversely, in the second step of the reaction, a proton is removed from C9 and is accepted by the histidine residue H232.

Structure

Lanosterol has three sets of and 25 alpha helices.

Disease

Lanosterol Synthase Inhibitors as Cholesterol Lowering Drugs: There has been increased awareness surrounding the use of lanosterol synthase inhibitors as drugs to reduce LDL (low-density lipoproteins) to aid in the treatment of atherosclerosis. The commonly prescribed statin drugs currently used to lower LDL (bad blood cholesterol) while less effectively increasing HDL (high-density lipoproteins), a good blood cholesterol, function by inhibiting the activity of HMG-CoA reductase. Since the lanosterol synthase enzyme catalyzes the creation of precursors upstream of cholesterol, statins could adversely affect the levels of intermediates essential for other biosynthesis pathways. So due to lanosterol synthase having a stronger association to cholesterol biosynthesis than HMG-CoA reductase, it can be considered a useful drug target.

Scientific publishings in which lanosterol synthase is inhibited in varying degrees have demonstrated a direct decline in both lanosterol development and HMG-CoA reductase activity.

Structural highlights

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References

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
3. ↑ Corey EJ, Cheng CH, Baker CH, Matsuda SPT, Li D, Song X (February 1997). "Studies on the Substrate Binding Segments and Catalytic Action of Lanosterol Synthase. Affinity Labeling with Carbocations Derived from Mechanism-Based Analogs of 2, 3-Oxidosqualene and Site-Directed Mutagenesis Probes". J. Am. Chem. Soc. 119 (6): 1289–96.