Biology:CYP4A11

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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 4A11 is a protein that in humans is codified by the CYP4A11 gene.[1][2]

Function

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates medium-chain fatty acids such as laurate and myristate.[2]

CYP4A11 is highly expressed in the liver and kidney.[3]

CYP4A11 along with CYP4A22, CYP4F2, and CYP4F3 metabolize arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) by an Omega oxidation reaction with the predominant 20-HETE-synthesizing enzymes in humans being CYP4F2 followed by CYP4A11; 20-HETE regulates blood flow, vascularization, blood pressure, and kidney tubule absorption of ions in rodents and possibly humans. [4] Gene polymorphism variants of CYP4A11 are associated with the development of hypertension and cerebral infarction (i.e. ischemic stroke) in humans (see 20-Hydroxyeicosatetraenoic acid).[5][6][7][8][9][10] In its capacity to form hydroxyl fatty acid, CYP4A11 is classified as a CYP monooxygease. Sesamin, the major lignan found in sesame, inhibits CYP4A11, which leads to decrease of plasma and urinary levels of 20-HETE. A study have found that sesamin inhibits human renal and liver microsome 20-HETE synthesis.[11]

CYP4A11 also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 19,20-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ isomers).[12] CYP4A11 does not convert arachidonic acid to epoxides. CYP4F8 and CYP4F12 likewise possess both monooxygenase activity for arachidonic acid and epoxygenase activity for docosahexaenoic and eicosapentaenoic acids. In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of 20-HETE, principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid, Epoxyeicosatetraenoic acid, and Epoxydocosapentaenoic acid sections on activities and clinical significance). These studies also indicate that the EPAs and EEQs are: 1) more potent than the CYP450 epoxygenase (e.g. CYP2C8, CYP2C9, CYP2C19, CYP2J2, and CYP2S1)-formed epoxides of arachidonic acid (termed EETs) in decreasing hypertension and pain perception; 2) more potent than or at least equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems.[13][14][15][16] Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans and in humans are by far the most prominent change in the profile of PUFA metabolites caused by dietary omega-3 fatty acids.[13][16][17]

Members of the CYP4A and CYP4F sub-families and CYP2U1 may also ω-hydroxylate and thereby reduce the activity of various fatty acid metabolites of arachidonic acid including LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins that are involved in regulating various inflammatory, vascular, and other responses in animals and humans.[18][19] This hydroxylation-induced inactivation may underlie the proposed roles of the cytochromes in dampening inflammatory responses and the reported associations of certain CYP4F2 and CYP4F3 single nucleotide variants with human Krohn's disease and Coeliac disease, respectively.[20][21][22]

T8590C single nucleotide polymorphism (SNP), rs1126742,[23] in the CYPA411 gene produces a protein with significantly reduced catalytic activity due to a loss-of-function mechanism; this SNP has been associated with hypertension in some but not all population studies.[24] This result could be due to a decline in the production of EEQs and EPDs, which as indicated above, have blood pressure lowering actions.

References

  1. ↑ "Characterization of a cDNA encoding a human kidney, cytochrome P-450 4A fatty acid omega-hydroxylase and the cognate enzyme expressed in Escherichia coli". Biochimica et Biophysica Acta 1172 (1–2): 161–6. Feb 1993. doi:10.1016/0167-4781(93)90285-L. PMID 7679927. 
  2. ↑ 2.0 2.1 "Entrez Gene: CYP4A11 cytochrome P450, family 4, subfamily A, polypeptide 11". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1579. 
  3. ↑ Johnson, A. L.; Edson, K. Z.; Totah, R. A.; Rettie, A. E. (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. 
  4. ↑ "Vascular actions of 20-HETE". Prostaglandins & Other Lipid Mediators 120: 9–16. Jul 2015. doi:10.1016/j.prostaglandins.2015.03.002. PMID 25813407. 
  5. ↑ "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation 111 (1): 63–9. 2005. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369. 
  6. ↑ "Association of a CYP4A11 variant and blood pressure in black men". Journal of the American Society of Nephrology 19 (8): 1606–12. Aug 2008. doi:10.1681/ASN.2008010063. PMID 18385420. 
  7. ↑ "A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men". Journal of Hypertension 26 (3): 453–61. Mar 2008. doi:10.1097/HJH.0b013e3282f2f10c. PMID 18300855. 
  8. ↑ "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension 46 (4): 766–71. 2005. doi:10.1161/01.HYP.0000182658.04299.15. PMID 16144986. 
  9. ↑ "A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population". Hypertension 52 (6): 1142–8. Dec 2008. doi:10.1161/HYPERTENSIONAHA.108.114082. PMID 18936345. 
  10. ↑ "Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population". Pharmacogenetics and Genomics 20 (3): 187–94. Mar 2010. doi:10.1097/FPC.0b013e328336eefe. PMID 20130494. 
  11. ↑ Wu, J. H.; Hodgson, J. M.; Clarke, M. W.; Indrawan, A. P.; Barden, A. E.; Puddey, I. B.; Croft, K. D. (2009). "Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: In vitro and human studies". Hypertension 54 (5): 1151–8. doi:10.1161/HYPERTENSIONAHA.109.139352. PMID 19786646. 
  12. ↑ "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators 96 (1–4): 99–108. Nov 2011. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326. 
  13. ↑ 13.0 13.1 "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews 66 (4): 1106–40. Oct 2014. doi:10.1124/pr.113.007781. PMID 25244930. 
  14. ↑ "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research 53: 108–23. Jan 2014. doi:10.1016/j.plipres.2013.11.003. PMID 24345640. 
  15. ↑ "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–13. Dec 2015. doi:10.1111/1753-0407.12358. PMID 26621325. 
  16. ↑ 16.0 16.1 "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators 113-115: 2–12. Oct 2014. doi:10.1016/j.prostaglandins.2014.09.001. PMID 25240260. 
  17. ↑ "Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway". Journal of Lipid Research 55 (6): 1150–1164. Mar 2014. doi:10.1194/jlr.M047357. PMID 24634501. 
  18. ↑ "Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3)". Archives of Biochemistry and Biophysics 355 (2): 201–5. 1998. doi:10.1006/abbi.1998.0724. PMID 9675028. 
  19. ↑ "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology 75 (12): 2263–75. Jun 2008. doi:10.1016/j.bcp.2008.03.004. PMID 18433732. 
  20. ↑ "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics 14 (11): 1215–22. 2006. doi:10.1038/sj.ejhg.5201687. PMID 16835590. 
  21. ↑ "Human cytochrome P450 4F3: structure, functions, and prospects". Drug Metabolism and Drug Interactions 27 (2): 63–71. 2012. doi:10.1515/dmdi-2011-0037. PMID 22706230. 
  22. ↑ "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology 146 (4): 929–31. Apr 2014. doi:10.1053/j.gastro.2013.12.034. PMID 24406470. https://zenodo.org/record/896397. 
  23. ↑ "Rs1126742 - SNPedia". https://www.snpedia.com/index.php/Rs1126742. 
  24. ↑ Zordoky, B. N.; El-Kadi, A. O. (2010). "Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases". Pharmacology & Therapeutics 125 (3): 446–63. doi:10.1016/j.pharmthera.2009.12.002. PMID 20093140. 

External links

Further reading



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