CYP4A11

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CYP4A11
Identifiers
Aliases CYP4A11, CP4Y, CYP4A2, CYP4AII, cytochrome P450 family 4 subfamily A member 11
External IDs MGI: 88611 HomoloGene: 128044 GeneCards: 1579
EC number 1.14.13.205
RNA expression pattern
PBB GE CYP4A11 207407 x at tn.png

PBB GE CYP4A11 211231 x at tn.png

PBB GE CYP4A11 217319 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000778
NM_001319155

NM_010011

RefSeq (protein)

NP_000769.2

NP_034141.3

Location (UCSC) Chr 1: 46.93 – 46.94 Mb Chr 4: 115.52 – 115.53 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome P450 4A11 is a protein that in humans is encoded by the CYP4A11 gene.[1][2]

Function[edit]

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.

CYP4A11 also has epoxygenase activity in that it metablizes 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).[11] 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 eicosapentenoic 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.[12][13][14][15] 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.[12][15][16]

Members of the CYP4A and CYP4F sub-families and CYPU21 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.[17][18] 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.[19][20][21]

T8590C single nucleotide polymorphism (SNP), rs1126742,[22] 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.[23] 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[edit]

  1. ^ Palmer CN, Richardson TH, Griffin KJ, Hsu MH, Muerhoff AS, Clark JE, Johnson EF (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): 161–6. doi:10.1016/0167-4781(93)90285-L. PMID 7679927. 
  2. ^ a b "Entrez Gene: CYP4A11 cytochrome P450, family 4, subfamily A, polypeptide 11". 
  3. ^ Johnson, A. L.; Edson, K. Z.; Totah, R. A.; Rettie, A. E. (2015). "Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer". Advances in pharmacology (San Diego, Calif.). Advances in Pharmacology 74: 223–62. doi:10.1016/bs.apha.2015.05.002. ISBN 9780128031193. PMC 4667791. PMID 26233909.  |chapter= ignored (help)
  4. ^ 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. 
  5. ^ Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O'Donnell CJ, Brown NJ, Waterman MR, Capdevila JH (2005). "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation 111 (1): 63–9. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369. 
  6. ^ Gainer JV, Lipkowitz MS, Yu C, Waterman MR, Dawson EP, Capdevila JH, Brown NJ (Aug 2008). "Association of a CYP4A11 variant and blood pressure in black men". Journal of the American Society of Nephrology 19 (8): 1606–12. doi:10.1681/ASN.2008010063. PMC 2488260. PMID 18385420. 
  7. ^ Fu Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Shindo A, Ohta M, Soma M, Aoi N, Sato M, Ozawa Y, Ma Y (Mar 2008). "A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men". Journal of Hypertension 26 (3): 453–61. doi:10.1097/HJH.0b013e3282f2f10c. PMID 18300855. 
  8. ^ Mayer B, Lieb W, Götz A, König IR, Aherrahrou Z, Thiemig A, Holmer S, Hengstenberg C, Doering A, Loewel H, Hense HW, Schunkert H, Erdmann J (2005). "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension 46 (4): 766–71. doi:10.1161/01.HYP.0000182658.04299.15. PMID 16144986. 
  9. ^ Sugimoto K, Akasaka H, Katsuya T, Node K, Fujisawa T, Shimaoka I, Yasuda O, Ohishi M, Ogihara T, Shimamoto K, Rakugi H (Dec 2008). "A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population". Hypertension 52 (6): 1142–8. doi:10.1161/HYPERTENSIONAHA.108.114082. PMID 18936345. 
  10. ^ Ding H, Cui G, Zhang L, Xu Y, Bao X, Tu Y, Wu B, Wang Q, Hui R, Wang W, Dackor RT, Kissling GE, Zeldin DC, Wang DW (Mar 2010). "Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population". Pharmacogenetics and Genomics 20 (3): 187–94. doi:10.1097/FPC.0b013e328336eefe. PMC 3932492. PMID 20130494. 
  11. ^ 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. 
  12. ^ 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): 1106–40. doi:10.1124/pr.113.007781. PMID 25244930. 
  13. ^ Zhang G, Kodani S, Hammock BD (Jan 2014). "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research 53: 108–23. doi:10.1016/j.plipres.2013.11.003. PMC 3914417. PMID 24345640. 
  14. ^ He J, Wang C, Zhu Y, Ai D (Dec 2015). "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–13. doi:10.1111/1753-0407.12358. PMID 26621325. 
  15. ^ 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. 
  16. ^ Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH (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. 
  17. ^ Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M (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. 
  18. ^ Hardwick JP (Jun 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. 
  19. ^ Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C (2006). "A functional candidate screen for coeliac disease genes". European Journal of Human Genetics : EJHG 14 (11): 1215–22. doi:10.1038/sj.ejhg.5201687. PMID 16835590. 
  20. ^ 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. 
  21. ^ Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK (Apr 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. 
  22. ^ https://www.snpedia.com/index.php/Rs1126742
  23. ^ 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. 

Further reading[edit]

  • Kawashima H, Kusunose E, Kubota I, Maekawa M, Kusunose M (Jan 1992). "Purification and NH2-terminal amino acid sequences of human and rat kidney fatty acid omega-hydroxylases". Biochimica et Biophysica Acta 1123 (2): 156–62. doi:10.1016/0005-2760(92)90106-6. PMID 1739747. 
  • Kawashima H, Kusunose E, Kikuta Y, Kinoshita H, Tanaka S, Yamamoto S, Kishimoto T, Kusunose M (Jul 1994). "Purification and cDNA cloning of human liver CYP4A fatty acid omega-hydroxylase". Journal of Biochemistry 116 (1): 74–80. PMID 7798189. 
  • Imaoka S, Ogawa H, Kimura S, Gonzalez FJ (Dec 1993). "Complete cDNA sequence and cDNA-directed expression of CYP4A11, a fatty acid omega-hydroxylase expressed in human kidney". DNA and Cell Biology 12 (10): 893–9. doi:10.1089/dna.1993.12.893. PMID 8274222. 
  • Bell DR, Plant NJ, Rider CG, Na L, Brown S, Ateitalla I, Acharya SK, Davies MH, Elias E, Jenkins NA (Aug 1993). "Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP4A cDNAs". The Biochemical Journal 294 (1): 173–80. doi:10.1042/bj2940173. PMC 1134581. PMID 8363569. 
  • Powell PK, Wolf I, Lasker JM (Nov 1996). "Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes". Archives of Biochemistry and Biophysics 335 (1): 219–26. doi:10.1006/abbi.1996.0501. PMID 8914854. 
  • Powell PK, Wolf I, Jin R, Lasker JM (Jun 1998). "Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11". The Journal of Pharmacology and Experimental Therapeutics 285 (3): 1327–36. PMID 9618440. 
  • Chang YT, Loew GH (Feb 1999). "Homology modeling and substrate binding study of human CYP4A11 enzyme". Proteins 34 (3): 403–15. doi:10.1002/(SICI)1097-0134(19990215)34:3<403::AID-PROT12>3.0.CO;2-D. PMID 10024026. 
  • Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK (Feb 2000). "Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11". The Journal of Biological Chemistry 275 (6): 4118–26. doi:10.1074/jbc.275.6.4118. PMID 10660572. 
  • Kawashima H, Naganuma T, Kusunose E, Kono T, Yasumoto R, Sugimura K, Kishimoto T (Jun 2000). "Human fatty acid omega-hydroxylase, CYP4A11: determination of complete genomic sequence and characterization of purified recombinant protein". Archives of Biochemistry and Biophysics 378 (2): 333–9. doi:10.1006/abbi.2000.1831. PMID 10860550. 
  • Hoch U, Ortiz De Montellano PR (Apr 2001). "Covalently linked heme in cytochrome p4504a fatty acid hydroxylases". The Journal of Biological Chemistry 276 (14): 11339–46. doi:10.1074/jbc.M009969200. PMID 11139583. 
  • Gonzalez MC, Marteau C, Franchi J, Migliore-Samour D (Nov 2001). "Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation". The British Journal of Dermatology 145 (5): 749–57. doi:10.1046/j.1365-2133.2001.04490.x. PMID 11736898. 
  • LeBrun LA, Hoch U, Ortiz de Montellano PR (Apr 2002). "Autocatalytic mechanism and consequences of covalent heme attachment in the cytochrome P4504A family". The Journal of Biological Chemistry 277 (15): 12755–61. doi:10.1074/jbc.M112155200. PMID 11821421. 
  • Savas U, Hsu MH, Johnson EF (Jan 2003). "Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone". Archives of Biochemistry and Biophysics 409 (1): 212–20. doi:10.1016/S0003-9861(02)00499-X. PMID 12464261. 
  • Bellamine A, Wang Y, Waterman MR, Gainer JV, Dawson EP, Brown NJ, Capdevila JH (Jan 2003). "Characterization of the CYP4A11 gene, a second CYP4A gene in humans". Archives of Biochemistry and Biophysics 409 (1): 221–7. doi:10.1016/S0003-9861(02)00545-3. PMID 12464262. 
  • Jin P, Fu GK, Wilson AD, Yang J, Chien D, Hawkins PR, Au-Young J, Stuve LL (Apr 2004). "PCR isolation and cloning of novel splice variant mRNAs from known drug target genes". Genomics 83 (4): 566–71. doi:10.1016/j.ygeno.2003.09.023. PMID 15028279. 
  • Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ (Sep 2004). "CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes". Drug Metabolism and Disposition 32 (9): 930–6. PMID 15319333. 
  • Gainer JV, Bellamine A, Dawson EP, Womble KE, Grant SW, Wang Y, Cupples LA, Guo CY, Demissie S, O'Donnell CJ, Brown NJ, Waterman MR, Capdevila JH (Jan 2005). "Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension". Circulation 111 (1): 63–9. doi:10.1161/01.CIR.0000151309.82473.59. PMID 15611369. 
  • Mayer B, Lieb W, Götz A, König IR, Aherrahrou Z, Thiemig A, Holmer S, Hengstenberg C, Doering A, Loewel H, Hense HW, Schunkert H, Erdmann J (Oct 2005). "Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy". Hypertension 46 (4): 766–71. doi:10.1161/01.HYP.0000182658.04299.15. PMID 16144986.