CYP4F3

Cytochrome P450 4F3, also 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]

CYP4F3
Identifiers
Aliases	CYP4F3, CPF3, CYP4F, LTB4H, cytochrome P450 family 4 subfamily F member 3, CYPIVF3
External IDs	OMIM: 601270; MGI: 2158641; HomoloGene: 73902; GeneCards: CYP4F3; OMA:CYP4F3 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.12 Start 15,640,897 bp[1] End 15,662,825 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 B1 Start 33,143,662 bp[2] End 33,166,376 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver trabecular bone blood bone marrow kidney tubule bone marrow cells metanephric glomerulus jejunal mucosa gallbladder human kidney Top expressed in granulocyte neural layer of retina right kidney yolk sac duodenum muscle of thigh jejunum left lobe of liver lip proximal tubule More reference expression data BioGPS n/a
Gene ontology Molecular function iron ion binding alpha-tocopherol omega-hydroxylase activity tocopherol omega-hydroxylase activity metal ion binding monooxygenase activity heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen oxidoreductase activity 20-hydroxy-leukotriene B4 omega oxidase activity leukotriene-B4 20-monooxygenase activity 20-aldehyde-leukotriene B4 20-monooxygenase activity Cellular component integral component of membrane organelle membrane endoplasmic reticulum membrane membrane intracellular membrane-bounded organelle endoplasmic reticulum Biological process leukotriene metabolic process lipid metabolism icosanoid metabolic process leukotriene B4 catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4051 170716 Ensembl ENSG00000186529 ENSMUSG00000024055 UniProt Q08477 n/a RefSeq (mRNA) NM_000896 NM_001199208 NM_001199209 NM_001369696 NM_130882 RefSeq (protein) NP_000887 NP_001186137 NP_001186138 NP_001356625 n/a Location (UCSC) Chr 19: 15.64 – 15.66 Mb Chr 17: 33.14 – 33.17 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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^[10] CYP3FA is the major enzyme accomplishing these omega oxidations in leukocytes.^[10]

CYP4F3A and/or CYP43FB 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]

Genetic variants

The hydroxylation-induced inactivation of the mediators of inflammation, 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 Crohn's disease (SNPs are designated rs1290617^[11] and rs1290620^[12] and celiac disease (rs1290622 and rs1290625).^{[8][13][14][15][16]}

There is also a study that have found an association within Guangzhou population between the single nucleotide variation rs3794987 and susceptibility to the SARS-CoV-1 virus, discovered in 2003. The GG/AG genotype was associated with an increased susceptibility to SARS-CoV-1, comparing to the AA genotype. However, the results of this association were not replicated in another study, on the Beijing population. The combined analysis of the two studies does not show any association of the CYP4F3 SNPs analyzed with SARS-CoV-1 susceptibility.^[17]

References

1. GRCh38: Ensembl release 89: ENSG00000186529 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024055 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. doi:10.1016/S0021-9258(18)98360-2. PMID 8486631.
6. 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.
7. "Entrez Gene: CYP4F3 cytochrome P450, family 4, subfamily F, polypeptide 3".
8. Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, et al. (April 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. S2CID 5258044.
9. 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.
10. 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. Vol. 74. pp. 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 9780128031193. PMC 4667791. PMID 26233909.
11. "Rs1290617". SNPedia.
12. "Reference SNP (refSNP) Cluster Report: rs1290620".
13. Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (November 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. S2CID 10054589.
14. 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.
15. Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, et al. (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.
16. 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.
17. Zhu X, Wang Y, Zhang H, Liu X, Chen T, Yang R, et al. (2011). "Genetic variation of the human α-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection". PLOS ONE. 6 (8): e23730. Bibcode:2011PLoSO...623730Z. doi:10.1371/journal.pone.0023730. PMC 3163911. PMID 21904596.

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. Bibcode:1994FEBSL.348...70K. doi:10.1016/0014-5793(94)00587-7. PMID 8026587. S2CID 83948293.
• 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. S2CID 307381.
• Christmas P, Jones JP, Patten CJ, Rock DA, Zheng Y, Cheng SM, et al. (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, et al. (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. S2CID 31914930.
• 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, et al. (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.