CYP4F3
Leukotriene-B(4) omega-hydroxylase 2 is an enzyme that in humans is encoded by the CYP4F3 gene.[5][6][7] CYP4F3 encodes two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule; selection of either isoform is tissue-specific with CYP3F3A being expressed mostly in leukocytes and CYP4F3B mostly in the liver.[8]
Function
The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, fatty acids and other lipids. CYP4F3 actually encodes two splice-variants, CYP4F3A and CYP4F3B, of the cytochrome P450 superfamily of enzymes. The gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F8, is approximately 18 kb away.[7] Both variants localize on the endoplasmic reticulum and metabolize leukotriene B4 and very likely 5-hydroxyeicosatetraenoic acid, 5-oxo-eicosatetraenoic acid, and 12-hydroxyeicosatetraenoic acid by an omega oxidation reaction, i.e. by adding a hydroxyl residue to their terminal (i.e. C-20) carbon.[9] This addition starts the process of inactivating and degrading all of these well-known mediators of inflammation and/or allergy.[10] CYP3FA is the major enzyme accomplishing these omega oxidations in leukocytes.[10] The hydroxylation-induced inactivation of these mediators, perhaps particularly of leukotriene B4, may underlie the proposed roles of these cytochromes in dampening inflammatory responses as well as the reported associations of certain CYP4F3 single nucleotide variants (SNPs) with human Krohn's disease (SNPs are designated Rs1290617[11] and rs1290620[12] and Celiac disease (rs1290622 and rs1290625).[8][13][14][14][15][16]
CYP4F3A and/or CYP43B also omega oxidize arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) as well as epoxyeicosatrienoic acids (EETs) to 20-hydroxy-EETs.[10] 20-HETE regulates blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans;[8] it has also been proposed to be involved in regulating the growth of various types of human cancers (see 20-Hydroxyeicosatetraenoic acid#cancer). EETS have a similar set of regulatory functions but often act in a manner opposite to 20-HETE (see epoxyeicosatrienoic acid#cancer); since, however, the activities of the 20-HEETs have not been well-defined, the function of EET omega oxidation is unclear.[8]
References
- GRCh38: Ensembl release 89: ENSG00000186529 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000024055 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Kikuta Y, Kusunose E, Endo K, Yamamoto S, Sogawa K, Fujii-Kuriyama Y, Kusunose M (May 1993). "A novel form of cytochrome P-450 family 4 in human polymorphonuclear leukocytes. cDNA cloning and expression of leukotriene B4 omega-hydroxylase". The Journal of Biological Chemistry. 268 (13): 9376–80. PMID 8486631.
- Kikuta Y, Kato M, Yamashita Y, Miyauchi Y, Tanaka K, Kamada N, Kusunose M (March 1998). "Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization". DNA and Cell Biology. 17 (3): 221–30. doi:10.1089/dna.1998.17.221. PMID 9539102.
- "Entrez Gene: CYP4F3 cytochrome P450, family 4, subfamily F, polypeptide 3".
- Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP (2012). "Human cytochrome P450 4F3: structure, functions, and prospects". Drug Metabolism and Drug Interactions. 27 (2): 63–71. doi:10.1515/dmdi-2011-0037. PMID 22706230.
- Powell WS, Rokach J (April 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMC 5710736. PMID 25449650.
- Johnson AL, Edson KZ, Totah RA, Rettie AE (2015). "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer. Advances in Pharmacology. 74. pp. 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 9780128031193. PMC 4667791. PMID 26233909.
- "Rs1290617". SNPedia.
- "Reference SNP (refSNP) Cluster Report: rs1290620".
- Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (2006). "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics. 14 (11): 1215–22. doi:10.1038/sj.ejhg.5201687. PMID 16835590.
- Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK (April 2014). "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology. 146 (4): 929–31. doi:10.1053/j.gastro.2013.12.034. PMID 24406470.
- Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M (July 1998). "Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3)". Archives of Biochemistry and Biophysics. 355 (2): 201–5. doi:10.1006/abbi.1998.0724. PMID 9675028.
- Hardwick JP (June 2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology. 75 (12): 2263–75. doi:10.1016/j.bcp.2008.03.004. PMID 18433732.
Further reading
- Simpson AE (March 1997). "The cytochrome P450 4 (CYP4) family". General Pharmacology. 28 (3): 351–9. doi:10.1016/S0306-3623(96)00246-7. PMID 9068972.
- Kikuta Y, Kusunose E, Kondo T, Yamamoto S, Kinoshita H, Kusunose M (July 1994). "Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver". FEBS Letters. 348 (1): 70–4. doi:10.1016/0014-5793(94)00587-7. PMID 8026587.
- Christmas P, Ursino SR, Fox JW, Soberman RJ (July 1999). "Expression of the CYP4F3 gene. tissue-specific splicing and alternative promoters generate high and low K(m) forms of leukotriene B(4) omega-hydroxylase". The Journal of Biological Chemistry. 274 (30): 21191–9. doi:10.1074/jbc.274.30.21191. PMID 10409674.
- Christmas P, Jones JP, Patten CJ, Rock DA, Zheng Y, Cheng SM, Weber BM, Carlesso N, Scadden DT, Rettie AE, Soberman RJ (October 2001). "Alternative splicing determines the function of CYP4F3 by switching substrate specificity". The Journal of Biological Chemistry. 276 (41): 38166–72. doi:10.1074/jbc.M104818200. PMID 11461919.
- Christmas P, Carlesso N, Shang H, Cheng SM, Weber BM, Preffer FI, Scadden DT, Soberman RJ (July 2003). "Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter". The Journal of Biological Chemistry. 278 (27): 25133–42. doi:10.1074/jbc.M302106200. PMID 12709424.
- Mizukami Y, Sumimoto H, Takeshige K (January 2004). "Induction of cytochrome CYP4F3A in all-trans-retinoic acid-treated HL60 cells". Biochemical and Biophysical Research Communications. 314 (1): 104–9. doi:10.1016/j.bbrc.2003.12.062. PMID 14715252.
- Christmas P, Tolentino K, Primo V, Berry KZ, Murphy RC, Chen M, Lee DM, Soberman RJ (March 2006). "Cytochrome P-450 4F18 is the leukotriene B4 omega-1/omega-2 hydroxylase in mouse polymorphonuclear leukocytes: identification as the functional orthologue of human polymorphonuclear leukocyte CYP4F3A in the down-regulation of responses to LTB4". The Journal of Biological Chemistry. 281 (11): 7189–96. doi:10.1074/jbc.M513101200. PMID 16380383.