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SQUALENE MONOOXYGENASE

Todd D. Porter, Ph.D.

 

Squalene monooxygenase (formerly squalene epoxidase) catalyzes the second committed (and likely rate-limiting) step in cholesterol biosynthesis from farnesyl pyrophosphate, making it an attractive pharmacotherapeutic target in the management of hypercholesterolemia and resultant cardiovascular disease.  In neural tissue squalene monooxygenase plays an essential role in the synthesis of cholesterol necessary for myelin membranes, and has been identified as the site of inhibition by tellurium-containing compounds that cause a peripheral neuropathy.  But, despite its pivotal role in cholesterol biosynthesis, remarkably little is known about this enzyme, especially in man.

Studies in my laboratory are directed at generating structural and biochemical information on squalene monooxygenase that will help us to understand its mechanism of action, its interaction with other proteins in the cell, and its inhibition by tellurium- and selenium-containing compounds.

 

The Cholesterol Biosynthetic Pathway

 

Created with ISIS/Draw 

Key

Enzyme

E.C. No. (ExPASy Enzyme database entry)

KEGG Metabolic Pathways entry*

Notes

1 HMG-CoA synthase 4.1.3.5 MAP00072 Cytosolic form catalyzes the first step in cholesterol pathway.
2 HMG-CoA reductase 1.1.1.34 MAP00100 The initial regulated step in cholesterol synthesis.  Inhibited by the statins, a mainstay in the treatment of hypercholesterolemia.
3 Squalene synthase 2.5.1.21 MAP00100 The first enzyme in the "committed pathway" for cholesterol synthesis.
4 Squalene monooxygenase 1.14.99.7 MAP00100 Squalene epoxidase; a flavoprotein monooxygenase located on the endoplasmic reticulum.
5 Lanosterol synthase 5.4.99.7 MAP00100 Also called 2,3-oxidosqualene cyclase.
6 Lanosterol demethylase     A cytochrome P450 (CYP51); azole antibiotics such as miconazole (Micatin) selectively inhibit the yeast enzyme and block growth.
* This is an expanded and interactive version of the cholesterol biosynthetic pathway shown above.
Click here to view 3-D renderings of this pathway at the Terre Haute Center for Medical Education

 

Further Information on Squalene Monooxygenase

 

 

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Comments to Todd D. Porter, Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536-0082.  
Phone 859 257-1137; FAX 859 257-7564
Last Modified: December 02, 2001
Copyright 2000, University of Kentucky Chandler Medical Center