Biology:CYP4F3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Cytochrome P450 4F3, also leukotriene-B(4) omega-hydroxylase 2, is an enzyme that in humans is encoded by the CYP4F3 gene.[1][2][3] 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.[4]

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.[3] 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.[5] This addition starts the process of inactivating and degrading all of these well-known mediators of inflammation[6] CYP3FA is the major enzyme accomplishing these omega oxidations in leukocytes.[6]

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.[6] 20-HETE regulates blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans;[4] 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.[4]

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[7] and rs1290620[8] and Celiac disease (rs1290622 and rs1290625).[4][9][10][11][12]

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.[13]

References

  1. ↑ "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. May 1993. doi:10.1016/S0021-9258(18)98360-2. PMID 8486631. 
  2. ↑ "Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization". DNA and Cell Biology 17 (3): 221–30. March 1998. doi:10.1089/dna.1998.17.221. PMID 9539102. 
  3. ↑ 3.0 3.1 "Entrez Gene: CYP4F3 cytochrome P450, family 4, subfamily F, polypeptide 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4051. 
  4. ↑ 4.0 4.1 4.2 4.3 "Human cytochrome P450 4F3: structure, functions, and prospects". Drug Metabolism and Drug Interactions 27 (2): 63–71. April 2012. doi:10.1515/dmdi-2011-0037. PMID 22706230. 
  5. ↑ "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. April 2015. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650. 
  6. ↑ 6.0 6.1 6.2 "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer. Advances in Pharmacology. 74. 2015. pp. 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 9780128031193. 
  7. ↑ "Rs1290617". SNPedia. http://www.snpedia.com/index.php/Rs1290617. 
  8. ↑ "Reference SNP (refSNP) Cluster Report: rs1290620". https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1290620. 
  9. ↑ "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics 14 (11): 1215–22. November 2006. doi:10.1038/sj.ejhg.5201687. PMID 16835590. 
  10. ↑ "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology 146 (4): 929–31. April 2014. doi:10.1053/j.gastro.2013.12.034. PMID 24406470. https://zenodo.org/record/896397. 
  11. ↑ "Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3)". Archives of Biochemistry and Biophysics 355 (2): 201–5. July 1998. doi:10.1006/abbi.1998.0724. PMID 9675028. 
  12. ↑ "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology 75 (12): 2263–75. June 2008. doi:10.1016/j.bcp.2008.03.004. PMID 18433732. 
  13. ↑ "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. 2011. doi:10.1371/journal.pone.0023730. PMID 21904596. Bibcode: 2011PLoSO...623730Z. 

Further reading

  • "The cytochrome P450 4 (CYP4) family". General Pharmacology 28 (3): 351–9. March 1997. doi:10.1016/S0306-3623(96)00246-7. PMID 9068972. 
  • "Cloning and expression of a novel form of leukotriene B4 omega-hydroxylase from human liver". FEBS Letters 348 (1): 70–4. July 1994. doi:10.1016/0014-5793(94)00587-7. PMID 8026587. 
  • "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. July 1999. doi:10.1074/jbc.274.30.21191. PMID 10409674. 
  • "Alternative splicing determines the function of CYP4F3 by switching substrate specificity". The Journal of Biological Chemistry 276 (41): 38166–72. October 2001. doi:10.1074/jbc.M104818200. PMID 11461919. 
  • "Myeloid expression of cytochrome P450 4F3 is determined by a lineage-specific alternative promoter". The Journal of Biological Chemistry 278 (27): 25133–42. July 2003. doi:10.1074/jbc.M302106200. PMID 12709424. 
  • "Induction of cytochrome CYP4F3A in all-trans-retinoic acid-treated HL60 cells". Biochemical and Biophysical Research Communications 314 (1): 104–9. January 2004. doi:10.1016/j.bbrc.2003.12.062. PMID 14715252. 
  • "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. March 2006. doi:10.1074/jbc.M513101200. PMID 16380383. 



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