Cytochrome P450 4F2
Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins (PubMed:10660572, PubMed:10833273, PubMed:11997390, PubMed:17341693, PubMed:18574070, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids. Displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs) (PubMed:18577768). Participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10660572, PubMed:17341693, PubMed:18574070). Plays a role in the oxidative inactivation of eicosanoids, including both pro-inflammatory and anti-inflammatory mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several HETEs (PubMed:10660572, PubMed:10833273, PubMed:17341693, PubMed:18574070, PubMed:18577768, PubMed:8026587, PubMed:9799565). Catalyzes omega-hydroxylation of 3-hydroxy fatty acids (PubMed:18065749). Converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites (PubMed:15145985). Contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening (PubMed:16547005, PubMed:18182499). Plays an important role in vitamin metabolism by chain shortening. Catalyzes omega-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols, thus promoting retention of alpha-tocopherols in tissues (PubMed:11997390). Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation (PubMed:19297519, PubMed:24138531).
Involvement in disease
Coumarin resistance
CMRES
A condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement.
None
Disease susceptibility may be associated with variants affecting the gene represented in this entry. The variant Met-433 is associated with coumarin (the brand name of warfarin) resistance by increasing coumarin maintenance dose in patients on this anti-coagulant therapy. This is probably due to decreased activity of the phylloquinone omega-hydroxylase activity, leading to an increase in hepatic vitamin K levels that warfarin must antagonize (PubMed:24138531).
Pathway
Lipid metabolism; arachidonate metabolism.
Lipid metabolism; leukotriene B4 degradation.
Cofactor degradation; phylloquinone degradation.
Sequence Similarities
Belongs to the cytochrome P450 family.
Tissue Specificity
Liver. Also present in kidney: specifically expressed in the S2 and S3 segments of proximal tubules in cortex and outer medulla (PubMed:10660572).
Cellular localization
- Microsome membrane
- Peripheral membrane protein
- Endoplasmic reticulum membrane
- Peripheral membrane protein
Alternative names
Cytochrome P450 4F2, 20-hydroxyeicosatetraenoic acid synthase, Arachidonic acid omega-hydroxylase, CYPIVF2, Cytochrome P450-LTB-omega, Docosahexaenoic acid omega-hydroxylase, Leukotriene-B(4) 20-monooxygenase 1, Leukotriene-B(4) omega-hydroxylase 1, Phylloquinone omega-hydroxylase CYP4F2, 20-HETE synthase, CYP4F2