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词条 CYP4A11
释义

  1. Function

  2. References

  3. External links

  4. Further reading

{{Infobox_gene}}Cytochrome P450 4A11 is a protein that in humans is encoded 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.

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 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.[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

1. ^{{cite journal | vauthors = Palmer CN, Richardson TH, Griffin KJ, Hsu MH, Muerhoff AS, Clark JE, Johnson EF | title = Characterization of a cDNA encoding a human kidney, cytochrome P-450 4A fatty acid omega-hydroxylase and the cognate enzyme expressed in Escherichia coli | journal = Biochimica et Biophysica Acta | volume = 1172 | issue = 1-2 | pages = 161–6 | date = Feb 1993 | pmid = 7679927 | pmc = | doi = 10.1016/0167-4781(93)90285-L }}
2. ^1 {{cite web | title = Entrez Gene: CYP4A11 cytochrome P450, family 4, subfamily A, polypeptide 11| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1579| accessdate = }}
3. ^{{cite journal | pmid = 26233909 | pmc = 4667791 | year = 2015 | author1 = Johnson | first1 = A. L. | title = Cytochrome P450 Function and Pharmacological Roles in Inflammation and Cancer | journal = Advances in pharmacology (San Diego, Calif.) | volume = 74 | pages = 223–62 | last2 = Edson | first2 = K. Z. | last3 = Totah | first3 = R. A. | last4 = Rettie | first4 = A. E. | doi = 10.1016/bs.apha.2015.05.002 | series = Advances in Pharmacology | isbn = 9780128031193 }}
4. ^{{cite journal | vauthors = Hoopes SL, Garcia V, Edin ML, Schwartzman ML, Zeldin DC | title = Vascular actions of 20-HETE | journal = Prostaglandins & Other Lipid Mediators | volume = 120 | pages = 9–16 | date = Jul 2015 | pmid = 25813407 | pmc = 4575602 | doi = 10.1016/j.prostaglandins.2015.03.002 }}
5. ^{{cite journal | vauthors = 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 | title = Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension | journal = Circulation | volume = 111 | issue = 1 | pages = 63–9 | year = 2005 | pmid = 15611369 | doi = 10.1161/01.CIR.0000151309.82473.59 }}
6. ^{{cite journal | vauthors = Gainer JV, Lipkowitz MS, Yu C, Waterman MR, Dawson EP, Capdevila JH, Brown NJ | title = Association of a CYP4A11 variant and blood pressure in black men | journal = Journal of the American Society of Nephrology | volume = 19 | issue = 8 | pages = 1606–12 | date = Aug 2008 | pmid = 18385420 | pmc = 2488260 | doi = 10.1681/ASN.2008010063 }}
7. ^{{cite journal | vauthors = Fu Z, Nakayama T, Sato N, Izumi Y, Kasamaki Y, Shindo A, Ohta M, Soma M, Aoi N, Sato M, Ozawa Y, Ma Y | title = A haplotype of the CYP4A11 gene associated with essential hypertension in Japanese men | journal = Journal of Hypertension | volume = 26 | issue = 3 | pages = 453–61 | date = Mar 2008 | pmid = 18300855 | doi = 10.1097/HJH.0b013e3282f2f10c }}
8. ^{{cite journal | vauthors = 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 | title = Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy | journal = Hypertension | volume = 46 | issue = 4 | pages = 766–71 | year = 2005 | pmid = 16144986 | doi = 10.1161/01.HYP.0000182658.04299.15 }}
9. ^{{cite journal | vauthors = Sugimoto K, Akasaka H, Katsuya T, Node K, Fujisawa T, Shimaoka I, Yasuda O, Ohishi M, Ogihara T, Shimamoto K, Rakugi H | title = A polymorphism regulates CYP4A11 transcriptional activity and is associated with hypertension in a Japanese population | journal = Hypertension | volume = 52 | issue = 6 | pages = 1142–8 | date = Dec 2008 | pmid = 18936345 | doi = 10.1161/HYPERTENSIONAHA.108.114082 }}
10. ^{{cite journal | vauthors = 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 | title = Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population | journal = Pharmacogenetics and Genomics | volume = 20 | issue = 3 | pages = 187–94 | date = Mar 2010 | pmid = 20130494 | pmc = 3932492 | doi = 10.1097/FPC.0b013e328336eefe }}
11. ^{{cite journal | vauthors = Westphal C, Konkel A, Schunck WH | title = CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? | journal = Prostaglandins & Other Lipid Mediators | volume = 96 | issue = 1–4 | pages = 99–108 | date = Nov 2011 | pmid = 21945326 | doi = 10.1016/j.prostaglandins.2011.09.001 }}
12. ^1 {{cite journal | vauthors = Fleming I | title = The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease | journal = Pharmacological Reviews | volume = 66 | issue = 4 | pages = 1106–40 | date = Oct 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 }}
13. ^{{cite journal | vauthors = Zhang G, Kodani S, Hammock BD | title = Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer | journal = Progress in Lipid Research | volume = 53 | pages = 108–23 | date = Jan 2014 | pmid = 24345640 | pmc = 3914417 | doi = 10.1016/j.plipres.2013.11.003 }}
14. ^{{cite journal | vauthors = He J, Wang C, Zhu Y, Ai D | title = Soluble epoxide hydrolase: A potential target for metabolic diseases | journal = Journal of Diabetes | volume = 8 | issue = 3 | pages = 305–13 | date = Dec 2015 | pmid = 26621325 | doi = 10.1111/1753-0407.12358 }}
15. ^1 {{cite journal | vauthors = Wagner K, Vito S, Inceoglu B, Hammock BD | title = The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling | journal = Prostaglandins & Other Lipid Mediators | volume = 113-115 | pages = 2–12 | date = Oct 2014 | pmid = 25240260 | pmc = 4254344 | doi = 10.1016/j.prostaglandins.2014.09.001 }}
16. ^{{cite journal | vauthors = 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 | title = Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway | journal = Journal of Lipid Research | volume = 55 | issue = 6 | pages = 1150–1164 | date = Mar 2014 | pmid = 24634501 | pmc = 4031946 | doi = 10.1194/jlr.M047357 }}
17. ^{{cite journal | vauthors = Kikuta Y, Kusunose E, Sumimoto H, Mizukami Y, Takeshige K, Sakaki T, Yabusaki Y, Kusunose M | title = Purification and characterization of recombinant human neutrophil leukotriene B4 omega-hydroxylase (cytochrome P450 4F3) | journal = Archives of Biochemistry and Biophysics | volume = 355 | issue = 2 | pages = 201–5 | year = 1998 | pmid = 9675028 | doi = 10.1006/abbi.1998.0724 }}
18. ^{{cite journal | vauthors = Hardwick JP | title = Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases | journal = Biochemical Pharmacology | volume = 75 | issue = 12 | pages = 2263–75 | date = Jun 2008 | pmid = 18433732 | doi = 10.1016/j.bcp.2008.03.004 }}
19. ^{{cite journal | vauthors = Curley CR, Monsuur AJ, Wapenaar MC, Rioux JD, Wijmenga C | title = A functional candidate screen for coeliac disease genes | journal = European Journal of Human Genetics | volume = 14 | issue = 11 | pages = 1215–22 | year = 2006 | pmid = 16835590 | doi = 10.1038/sj.ejhg.5201687 }}
20. ^{{cite journal | vauthors = Corcos L, Lucas D, Le Jossic-Corcos C, Dréano Y, Simon B, Plée-Gautier E, Amet Y, Salaün JP | title = Human cytochrome P450 4F3: structure, functions, and prospects | journal = Drug Metabolism and Drug Interactions | volume = 27 | issue = 2 | pages = 63–71 | pmid = 22706230 | doi = 10.1515/dmdi-2011-0037 | year = 2012 }}
21. ^{{cite journal | vauthors = Costea I, Mack DR, Lemaitre RN, Israel D, Marcil V, Ahmad A, Amre DK | title = Interactions between the dietary polyunsaturated fatty acid ratio and genetic factors determine susceptibility to pediatric Crohn's disease | journal = Gastroenterology | volume = 146 | issue = 4 | pages = 929–31 | date = Apr 2014 | pmid = 24406470 | doi = 10.1053/j.gastro.2013.12.034 }}
22. ^https://www.snpedia.com/index.php/Rs1126742
23. ^{{cite journal | pmid = 20093140 | year = 2010 | author1 = Zordoky | first1 = B. N. | title = Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases | journal = Pharmacology & Therapeutics | volume = 125 | issue = 3 | pages = 446–63 | last2 = El-Kadi | first2 = A. O. | doi = 10.1016/j.pharmthera.2009.12.002 }}

External links

  • {{UCSC gene info|CYP4A11}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Kawashima H, Kusunose E, Kubota I, Maekawa M, Kusunose M | title = Purification and NH2-terminal amino acid sequences of human and rat kidney fatty acid omega-hydroxylases | journal = Biochimica et Biophysica Acta | volume = 1123 | issue = 2 | pages = 156–62 | date = Jan 1992 | pmid = 1739747 | doi = 10.1016/0005-2760(92)90106-6 }}
  • {{cite journal | vauthors = Kawashima H, Kusunose E, Kikuta Y, Kinoshita H, Tanaka S, Yamamoto S, Kishimoto T, Kusunose M | title = Purification and cDNA cloning of human liver CYP4A fatty acid omega-hydroxylase | journal = Journal of Biochemistry | volume = 116 | issue = 1 | pages = 74–80 | date = Jul 1994 | pmid = 7798189 | doi = }}
  • {{cite journal | vauthors = Imaoka S, Ogawa H, Kimura S, Gonzalez FJ | title = Complete cDNA sequence and cDNA-directed expression of CYP4A11, a fatty acid omega-hydroxylase expressed in human kidney | journal = DNA and Cell Biology | volume = 12 | issue = 10 | pages = 893–9 | date = Dec 1993 | pmid = 8274222 | doi = 10.1089/dna.1993.12.893 }}
  • {{cite journal | vauthors = Bell DR, Plant NJ, Rider CG, Na L, Brown S, Ateitalla I, Acharya SK, Davies MH, Elias E, Jenkins NA | title = Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP4A cDNAs | journal = The Biochemical Journal | volume = 294 | issue = 1 | pages = 173–80 | date = Aug 1993 | pmid = 8363569 | pmc = 1134581 | doi = 10.1042/bj2940173}}
  • {{cite journal | vauthors = Powell PK, Wolf I, Lasker JM | title = Identification of CYP4A11 as the major lauric acid omega-hydroxylase in human liver microsomes | journal = Archives of Biochemistry and Biophysics | volume = 335 | issue = 1 | pages = 219–26 | date = Nov 1996 | pmid = 8914854 | doi = 10.1006/abbi.1996.0501 }}
  • {{cite journal | vauthors = Powell PK, Wolf I, Jin R, Lasker JM | title = Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 285 | issue = 3 | pages = 1327–36 | date = Jun 1998 | pmid = 9618440 | doi = }}
  • {{cite journal | vauthors = Chang YT, Loew GH | title = Homology modeling and substrate binding study of human CYP4A11 enzyme | journal = Proteins | volume = 34 | issue = 3 | pages = 403–15 | date = Feb 1999 | pmid = 10024026 | doi = 10.1002/(SICI)1097-0134(19990215)34:3<403::AID-PROT12>3.0.CO;2-D }}
  • {{cite journal | vauthors = Lasker JM, Chen WB, Wolf I, Bloswick BP, Wilson PD, Powell PK | title = Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 6 | pages = 4118–26 | date = Feb 2000 | pmid = 10660572 | doi = 10.1074/jbc.275.6.4118 }}
  • {{cite journal | vauthors = Kawashima H, Naganuma T, Kusunose E, Kono T, Yasumoto R, Sugimura K, Kishimoto T | title = Human fatty acid omega-hydroxylase, CYP4A11: determination of complete genomic sequence and characterization of purified recombinant protein | journal = Archives of Biochemistry and Biophysics | volume = 378 | issue = 2 | pages = 333–9 | date = Jun 2000 | pmid = 10860550 | doi = 10.1006/abbi.2000.1831 }}
  • {{cite journal | vauthors = Hoch U, Ortiz De Montellano PR | title = Covalently linked heme in cytochrome p4504a fatty acid hydroxylases | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 11339–46 | date = Apr 2001 | pmid = 11139583 | doi = 10.1074/jbc.M009969200 }}
  • {{cite journal | vauthors = Gonzalez MC, Marteau C, Franchi J, Migliore-Samour D | title = Cytochrome P450 4A11 expression in human keratinocytes: effects of ultraviolet irradiation | journal = The British Journal of Dermatology | volume = 145 | issue = 5 | pages = 749–57 | date = Nov 2001 | pmid = 11736898 | doi = 10.1046/j.1365-2133.2001.04490.x }}
  • {{cite journal | vauthors = LeBrun LA, Hoch U, Ortiz de Montellano PR | title = Autocatalytic mechanism and consequences of covalent heme attachment in the cytochrome P4504A family | journal = The Journal of Biological Chemistry | volume = 277 | issue = 15 | pages = 12755–61 | date = Apr 2002 | pmid = 11821421 | doi = 10.1074/jbc.M112155200 }}
  • {{cite journal | vauthors = Savas U, Hsu MH, Johnson EF | title = Differential regulation of human CYP4A genes by peroxisome proliferators and dexamethasone | journal = Archives of Biochemistry and Biophysics | volume = 409 | issue = 1 | pages = 212–20 | date = Jan 2003 | pmid = 12464261 | doi = 10.1016/S0003-9861(02)00499-X }}
  • {{cite journal | vauthors = Bellamine A, Wang Y, Waterman MR, Gainer JV, Dawson EP, Brown NJ, Capdevila JH | title = Characterization of the CYP4A11 gene, a second CYP4A gene in humans | journal = Archives of Biochemistry and Biophysics | volume = 409 | issue = 1 | pages = 221–7 | date = Jan 2003 | pmid = 12464262 | doi = 10.1016/S0003-9861(02)00545-3 }}
  • {{cite journal | vauthors = Jin P, Fu GK, Wilson AD, Yang J, Chien D, Hawkins PR, Au-Young J, Stuve LL | title = PCR isolation and cloning of novel splice variant mRNAs from known drug target genes | journal = Genomics | volume = 83 | issue = 4 | pages = 566–71 | date = Apr 2004 | pmid = 15028279 | doi = 10.1016/j.ygeno.2003.09.023 }}
  • {{cite journal | vauthors = Ramírez J, Innocenti F, Schuetz EG, Flockhart DA, Relling MV, Santucci R, Ratain MJ | title = CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes | journal = Drug Metabolism and Disposition | volume = 32 | issue = 9 | pages = 930–6 | date = Sep 2004 | pmid = 15319333 | doi = }}
  • {{cite journal | vauthors = 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 | title = Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension | journal = Circulation | volume = 111 | issue = 1 | pages = 63–9 | date = Jan 2005 | pmid = 15611369 | doi = 10.1161/01.CIR.0000151309.82473.59 }}
  • {{cite journal | vauthors = 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 | title = Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy | journal = Hypertension | volume = 46 | issue = 4 | pages = 766–71 | date = Oct 2005 | pmid = 16144986 | doi = 10.1161/01.HYP.0000182658.04299.15 }}
{{refend}}{{Cytochrome P450}}
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