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CYP4A11

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CYP4A11
Identifiers
AliasesCYP4A11, CP4Y, CYP4A2, CYP4AII, cytochrome P450 family 4 subfamily A member 11, CYPIVA11
External IDsOMIM: 601310; MGI: 88611; HomoloGene: 128044; GeneCards: CYP4A11; OMA:CYP4A11 - orthologs
EC number1.14.14.80
Orthologs
SpeciesHumanMouse
Entrez

1579

13117

Ensembl

ENSG00000187048

ENSMUSG00000066072

UniProt

Q02928

O88833

RefSeq (mRNA)

NM_000778
NM_001319155
NM_001363587

NM_010011

RefSeq (protein)

NP_000769
NP_001306084
NP_001350516

NP_034141

Location (UCSC)Chr 1: 46.93 – 46.94 MbChr 4: 115.38 – 115.39 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.[5][6]

Family

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This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases, catalyzing many reactions involved in drug metabolism as well as the synthesis of cholesterol, steroids, and other lipids.

Tissue and subcellular distribution

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CYP4A11 is highly expressed in the liver and kidney.[7] Its primary subcellular localization is in the endoplasmic reticulum, where it participates in the hydroxylation of medium-chain fatty acids such as laurate and myristate.[6]

Function

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CYP4A11 plays a crucial role in metabolizing arachidonic acid into 20-Hydroxyeicosatetraenoic acid (20-HETE) via an Omega oxidation reaction. In humans, the predominant enzymes synthesizing 20-HETE are CYP4F2 and CYP4A11.[8] 20-HETE regulates blood flow, vascularization, blood pressure, and renal ion absorption, particularly in rodents and potentially in humans.

In addition to its role in omega oxidation, CYP4A11 exhibits epoxygenase activity, converting docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs).[9] Notably, CYP4A11 does not convert arachidonic acid to epoxides, a function primarily performed by CYP2C and CYP2J subfamily members. EDPs and EEQs generally oppose the effects of 20-HETE, demonstrating potent actions in lowering blood pressure, inhibiting thrombosis and inflammation, and reducing cancer cell growth.[10][11][12][13]

Omega-3-rich diets significantly elevate serum and tissue levels of EDPs and EEQs in both animals and humans, making these metabolites the most prominent polyunsaturated fatty acid derivatives resulting from such diets.[10][13][14]

Members of the CYP4A and CYP4F subfamilies, along with CYP2U1, also ω-hydroxylate various fatty acid metabolites of arachidonic acid—including LTB4, 5-HETE, 5-oxo-eicosatetraenoic acid, 12-HETE, and several prostaglandins—thereby modulating inflammatory, vascular, and other biological responses.[15][16]

Clinical significance

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Polymorphisms in CYP4A11 are associated with susceptibility to hypertension and cerebral infarction (ischemic stroke) in humans.[17][18][19][20][21][22] The T8590C single nucleotide polymorphism (SNP), rs1126742,[23] results in a CYP4A11 variant with significantly reduced enzymatic activity, likely due to a loss-of-function mutation.[24] This variant may reduce the production of EEQs and EDPs, contributing to blood pressure dysregulation. Dietary sesamin, a major lignan in sesame, inhibits CYP4A11, reducing 20-HETE synthesis and lowering its plasma and urinary levels. This inhibition has been demonstrated in both in vitro and human studies.[25] Furthermore, hydroxylation-induced inactivation by CYP4A and CYP4F enzymes is implicated in modulating inflammation, potentially explaining the links between CYP4F2 and CYP4F3 variants and human Crohn's disease and Coeliac disease.[26][27][28]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000187048 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000066072 – 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. ^ Palmer CN, Richardson TH, Griffin KJ, Hsu MH, Muerhoff AS, Clark JE, et al. (Feb 1993). "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): 161–166. doi:10.1016/0167-4781(93)90285-L. PMID 7679927.
  6. ^ a b "Entrez Gene: CYP4A11 cytochrome P450, family 4, subfamily A, polypeptide 11".
  7. ^ Johnson AL, Edson KZ, Totah RA, Rettie AE (2015). "Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer". Advances in Pharmacology. Advances in Pharmacology. Vol. 74. pp. 223–262. doi:10.1016/bs.apha.2015.05.002. ISBN 978-0-12-803119-3. PMC 4667791. PMID 26233909.
  8. ^ Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC (Jul 2015). "Vascular actions of 20-HETE". Prostaglandins & Other Lipid Mediators. 120: 9–16. doi:10.1016/j.prostaglandins.2015.03.002. PMC 4575602. PMID 25813407.
  9. ^ Westphal C, Konkel A, Schunck WH (Nov 2011). "CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators. 96 (1–4): 99–108. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326.
  10. ^ a b Fleming I (Oct 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–1140. doi:10.1124/pr.113.007781. PMID 25244930. S2CID 39465144.
  11. ^ Zhang G, Kodani S, Hammock BD (Jan 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research. 53: 108–123. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640.
  12. ^ He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes. 8 (3): 305–313. doi:10.1111/1753-0407.12358. PMID 26621325.
  13. ^ a b Wagner K, Vito S, Inceoglu B, Hammock BD (Oct 2014). "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators. 113–115: 2–12. doi:10.1016/j.prostaglandins.2014.09.001. PMC 4254344. PMID 25240260.
  14. ^ Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, et al. (Mar 2014). "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. doi:10.1194/jlr.M047357. PMC 4031946. PMID 24634501.
  15. ^ Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, et al. (Jul 1998). "Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3)". Archives of Biochemistry and Biophysics. 355 (2): 201–205. doi:10.1006/abbi.1998.0724. PMID 9675028.
  16. ^ Hardwick JP (Jun 2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases". Biochemical Pharmacology. 75 (12): 2263–2275. doi:10.1016/j.bcp.2008.03.004. PMID 18433732.
  17. ^ Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, et al. (Jan 2005). "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation. 111 (1): 63–69. CiteSeerX 10.1.1.335.1764. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369.
  18. ^ Gainer JV, Lipkowitz MS, Yu C, Waterman MR, Dawson EP, Capdevila JH, et al. (Aug 2008). "Association of a CYP4A11 variant and blood pressure in black men". Journal of the American Society of Nephrology : JASN. 19 (8): 1606–1612. doi:10.1681/ASN.2008010063. PMC 2488260. PMID 18385420.
  19. ^ Fu Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Shindo A, et al. (Mar 2008). "A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men". Journal of Hypertension. 26 (3): 453–461. doi:10.1097/HJH.0b013e3282f2f10c. PMID 18300855. S2CID 23680415.
  20. ^ Mayer B, Lieb W, Götz A, König IR, Aherrahrou Z, Thiemig A, et al. (Oct 2005). "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension. 46 (4). Dallas, Tex.: 766–771. doi:10.1161/01.HYP.0000182658.04299.15. PMID 16144986.
  21. ^ Sugimoto K, Akasaka H, Katsuya T, Node K, Fujisawa T, Shimaoka I, et al. (Dec 2008). "A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population". Hypertension. 52 (6). Dallas, Tex.: 1142–1148. doi:10.1161/HYPERTENSIONAHA.108.114082. PMID 18936345.
  22. ^ Ding H, Cui G, Zhang L, Xu Y, Bao X, Tu Y, et al. (Mar 2010). "Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population". Pharmacogenetics and Genomics. 20 (3): 187–194. doi:10.1097/FPC.0b013e328336eefe. PMC 3932492. PMID 20130494.
  23. ^ "Rs1126742 - SNPedia".
  24. ^ Zordoky BN, El-Kadi AO (Mar 2010). "Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases". Pharmacology & Therapeutics. 125 (3): 446–463. doi:10.1016/j.pharmthera.2009.12.002. PMID 20093140.
  25. ^ Wu JH, Hodgson JM, Clarke MW, Indrawan AP, Barden AE, Puddey IB, et al. (Nov 2009). "Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: In vitro and human studies". Hypertension. 54 (5). Dallas, Tex.: 1151–1158. doi:10.1161/HYPERTENSIONAHA.109.139352. PMID 19786646. S2CID 207687898.
  26. ^ Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (Nov 2006). "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics : EJHG. 14 (11): 1215–1222. doi:10.1038/sj.ejhg.5201687. PMID 16835590.
  27. ^ Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, et al. (Apr 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.
  28. ^ Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, et al. (Apr 2014). "Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease". Gastroenterology. 146 (4): 929–931. doi:10.1053/j.gastro.2013.12.034. PMID 24406470.
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Further reading

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