Squalene monooxygenase
Encyclopedia
Squalene monooxygenase is an enzyme
that uses NADPH and molecular oxygen
to oxidize squalene
to 2,3-oxidosqualene
(squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in 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 gene
.
Note that SqMO is NOT the same as SqE.
hydroperoxides at the enzyme
active site
, which then transfer the terminal oxygen atom of the hydroperoxide to the substrate
. Squalene monooxygenase differs from other flavin monooxygenases in that the oxygen
is inserted as an epoxide
rather than as a hydroxyl
group. Squalene monooxygenase contains a loosely bound FAD
flavin
and obtains electrons from NADPH-cytochrome P450 reductase, rather than binding the nicotinamide
cofactor NADPH directly.
Inhibitors of squalene epoxidase have found application mainly as antifungal drug
s:
Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that uses NADPH and molecular oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
to oxidize squalene
Squalene
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though plant sources are used as well, including amaranth seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including humans...
to 2,3-oxidosqualene
2,3-Oxidosqualene
2,3- Oxidosqualene ' is an intermediate in the synthesis of the membrane sterol precursors lanosterol and cycloartenol, as well as saponins. It is formed from squalene by squalene monooxygenase...
(squalene epoxide). Squalene epoxidase catalyzes the first oxygenation step in sterol
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway. In humans, squalene epoxidase is encoded by the SQLE gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Note that SqMO is NOT the same as SqE.
Mechanism
Squalene monooxygenase is a flavoprotein monooxygenase. Flavoprotein monooxygenase form flavinFlavin
Flavin is the common name for a group of organic compounds based on pteridine, formed by the tricyclic heteronuclear organic ring isoalloxazine. The biochemical source is the vitamin riboflavin...
hydroperoxides at the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
, which then transfer the terminal oxygen atom of the hydroperoxide to the substrate
Substrate
Substrate may mean:*Substrate , Natural stone, masonry surface, ceramic and porcelain tiles*Substrate , the material used in the bottom of an aquarium*Substrate , the material used in the bottom of a vivarium or terrarium...
. Squalene monooxygenase differs from other flavin monooxygenases in that the oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
is inserted as an epoxide
Epoxide
An epoxide is a cyclic ether with three ring atoms. This ring approximately defines an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Simple epoxides are named from the parent compound ethylene oxide or oxirane, such as in...
rather than as a hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group. Squalene monooxygenase contains a loosely bound FAD
FAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
flavin
Flavin
Flavin is the common name for a group of organic compounds based on pteridine, formed by the tricyclic heteronuclear organic ring isoalloxazine. The biochemical source is the vitamin riboflavin...
and obtains electrons from NADPH-cytochrome P450 reductase, rather than binding the nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
cofactor NADPH directly.
Inhibitors
Note that SqMO is NOT the same as SqE, which is a later step in the pathway.Inhibitors of squalene epoxidase have found application mainly as antifungal drug
Antifungal drug
An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis , serious systemic infections such as cryptococcal meningitis, and others...
s:
- butenafineButenafineButenafine hydrochloride is a synthetic benzylamine antifungal, marketed under the trade names Mentax, Butop and is the active ingredient in Schering-Plough's Lotrimin Ultra. It is structurally related to synthetic allylamine antifungals such as terbinafine.-Pharmacology:Butenafine hydrochloride...
- naftifineNaftifineNaftifine is an allylamine antifungal drug for the topical treatment of tinea pedis, tinea cruris, and tinea corporis ....
- terbinafineTerbinafineTerbinafine hydrochloride is a...
Since squalene epoxidase is on the biosynthetic pathway leading to cholesterol, inhibitors of this enzyme may also find application in treatment of hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
.