Leukotriene-B(4) omega-hydroxylase 1 is an enzyme protein involved in the metabolism of various endogenous substrates (mainly the fatty acids) and xenobiotics (including pharmaceutical drugs). The most notable substrate of the enzyme is leukotriene B4, a potent mediator of inflammation. The CYP4F2 gene encodes the enzyme in humans.
Function
The Leukotriene-B(4) omega-hydroxylase 1, or simply the CYP4F2 enzyme protein, encoded by CYP4F2 gene in humans, is a member of the cytochrome P450 superfamily of enzymes. The CYP4F2 gene belongs to a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F11, is approximately 16 kb away.
The enzyme is called Leukotriene-B(4) omega-hydroxylase 1 because it starts the process of inactivating and degrading leukotriene B4, a potent mediator of inflammation.
The cytochrome P450 enzymes are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids, and other lipids.
The CYP4F2 enzyme protein presents in endoplasmic reticulum.
The enzyme CYP4F2 is involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins. It controls the bioavailability of Vitamin E. It also controls the bioavailability of Vitamin K, a co-factor required for blood to clot. Variations in the CYP4F2 gene that affect the bioavailability of Vitamin K also affect the dosing of Vitamin K antagonists such as warfarin, coumarin or acenocoumarol. The enzyme also regulates the bioactivation of various drugs, e.g., the anti-malarial drug pafuramidine and the anti-parasitic drug furamidine. It also plays a role in renal water homeostasis.
Inactivation of Leukotriene B4
Arachidonic acid is a precursor of the eicosanoid molecules that control immune response and inflammation. Acute inflammation on injury or infection protects the body from pathogens. It should also be taken into consideration that if inflammation is continuing for a notably long time, healthy cells and tissues are damaged. Thus, the inflammation must be carefully controlled. Leukotriene B4 is a pro-inflammatory eicosanoid with strong chemoattractant properties. It can be rapidly produced by activated innate immune cells, such as neutrophils, macrophages and mast cells. It induces the activation of polymorphonuclear leukocytes, monocytes and fibroblasts, the production of superoxide and the release of cytokines to attract neutrophils. CYP4F2 starts the process of inactivating and degrading leukotriene B4, by converting it to its ω-hydroxylated metabolite 20-hydroxyleukotriene B4 in human liver microsomes. CYP4F2 then coverts 20-hydroxyleukotriene B4 to 20-oxoleukotriene B4 and then to 20-carboxyleukotrene B4.
Chain shortening
It is α-, β-, and ω-oxidation of fatty acid carbon chains that degrades the acids, with the preferred pathway being the β-oxidation in the mitochondria and peroxisomes. Very long chain fatty acids cannot be β-oxidized. The number of carbon atoms in the chains of such acids exceeds 22. Such chains must be shortened before being oxidized by mitochondria. The CYP4F2 enzyme is involved in catalyzing the ω-oxidation and chain shortening of such acids.
Metabolism of vitamins
The enzyme plays an important role in vitamin metabolism by chain shortening.
CYP4F2 is the only known enzyme to ω-hydroxylate tocotrienols and tocopherols (types of Vitamin E), thus making it a key regulator of circulating plasma Vitamin E levels. It catalyzes ω-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over α-tocopherols, thus promoting retention of α-tocopherols in tissues.
Both types of Vitamin K (K1 and K2) can be used as co-factors for γ-glutamyl carboxylase, an enzyme that catalyzes the posttranslational modification of Vitamin K-dependent proteins, thus biochemically activating the proteins involved in blood coagulation and bone mineralization. CYP4F2 ω-xydroxylates and inactivates Vitamin K. As a result, CYP4F2 becomes vital negative regulator of circulating Vitamin K levels.