Squalene monooxygenase

Squalene monooxygenase is an is_associated_with::enzyme that uses is_associated_with::NADPH and molecular is_associated_with::oxygen to oxidize is_associated_with::squalene to is_associated_with::2,3-oxidosqualene (squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in is_associated_with::sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE is_associated_with::gene. Squalene monooxygenase (SqMO) was formerly referred to as squalene epoxidase (SqE) in the literature.

Mechanism
Squalene monooxygenase is a is_associated_with::flavoprotein is_associated_with::monooxygenase. Flavoprotein monooxygenase form flavin is_associated_with::hydroperoxides at the is_associated_with::enzyme is_associated_with::active site, which then transfer the terminal is_associated_with::oxygen atom of the is_associated_with::hydroperoxide to the substrate. Squalene monooxygenase differs from other flavin monooxygenases in that the is_associated_with::oxygen is inserted as an is_associated_with::epoxide rather than as a is_associated_with::hydroxyl group. Squalene monooxygenase contains a loosely bound is_associated_with::FAD flavin and obtains is_associated_with::electrons from is_associated_with::NADPH-is_associated_with::cytochrome P450 reductase, rather than binding the is_associated_with::nicotinamide cofactor NADPH directly.

Inhibitors
Inhibitors of squalene epoxidase have found application mainly as is_associated_with::antifungal drugs:


 * is_associated_with::butenafine
 * is_associated_with::naftifine
 * is_associated_with::terbinafine

Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of is_associated_with::hypercholesterolemia.

Localization
In yeast Saccharomyces cerevisiae, squalene epoxidase is localized to both the endoplasmic reticulum and lipid droplets. Only the ER localized protein is active.

Additional products
Squalene epoxidase also catalyzes the formation of diepoxysqualene (DOS). DOS is converted to 24(S),25-epoxylanosterol by lanosterol synthase.

Model organisms
is_associated_with::Model organisms have been used in the study of SQLE function. A conditional is_associated_with::knockout mouse line called Sqletm1a(EUCOMM)Wtsi was generated at the is_associated_with::Wellcome Trust Sanger Institute. Male and female animals underwent a standardized is_associated_with::phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping

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