ALOXE3

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Epidermis-type lipoxygenase 3 (ALOXE3 or eLOX3) is a member of the lipoxygenase family of enzymes; in humans, it is encoded by the ALOXE3 gene.[1] This gene is located on chromosome 17 at position 13.1 where it forms a cluster with two other lipoxygenases, ALOX12B and ALOX15B.[2] Among the human lipoxygenases, ALOXE3 is most closely (54% identity) related in amino acid sequence to ALOX12B.[3][4][5] ALOXE3, ALOX12B, and ALOX15B are often classified as epidermal lipoxygenases, in distinction to the other three human lipoxygenases (ALOX5, ALOX12, and ALOX15), because they were initially defined as being highly or even exclusively expressed and functioning in skin. The epidermis-type lipoxygenases are now regarded as a distinct subclass within the multigene family of mammalian lipoxygenases with mouse Aloxe3 (also termed e-Lox-3) being the ortholog to human ALOXE3, mouse Alox12b being the ortholog to human ALOX12B (MIM 603741), and mouse Alox8 being the ortholog to human ALOX15B (MIM 603697)[supplied by OMIM].[1] ALOX12B and ALOXE3 in humans, Alox12b and Aloxe3 in mice, and comparable orthologs in other in other species are proposed to act sequentially in a multistep metabolic pathway that forms products that are structurally critical for creating and maintaining the skin's water barrier function.

Tissue distribution

Immunologically detected ALOXE3 and ALOX12B in humans and Aloxe3 and Alox12b in mice have a similar tissue distribution in being highly expressed in the outer, differentiated layers of the epidermis; they co-localize at the surface of keratinocytes in the stratum granulosum of mouse skin and during mouse embryogenesis appear concurrently at the onset of skin development at day 15.5.[6] ALOXE3 mRNA in humans was also detected at low levels in the pancreas, ovary, brain, testis, placenta, and some secretory epithelia.[6][7] Aloxe3 and Alox12b mRNA was detected in the tongue, forestomach, trachea, brain, testis, and adipose tissue of mice and in the spinal cord of rats.[6]

Activity

Epidermal tissue

ALOX12B, like most of the other lipoxygenases, possesses dioxygenase (EC 1.13.11) activity: it catalyzes the incorporate dioxygen (i.e. molecular oxygen [O2]) into a single substrate. Owing to this activity, the enzyme adds (O2) in the form of a hydroperoxyl (HO2) residue to arachidonic acid at its 12th carbon thereby forming 12(R)-hydroperoxy-5Z,8Z,10E,14Z-icosatetraenoic acid (also termed 12(R)-HpETE or 12R-HpETE).[8][9]

arachidonic acid + O2 <math>\rightleftharpoons</math> 12R-HpETE

Hydroperoxy-containing polyunsaturated fatty acids (PUFAs) such as 12R-HETE readily breakdown through non-enzymatic transformations in which the two oxygen atoms of the hydroperoxy residue rearrange to form PUFAs containing one hydroxyl (also termed alcohol) residue and one epoxide residue.[10] This transformation may occur in tissues or during tissue preparations with 12-HpETE to form Hepoxilins, i.e. epoxyalcohols of 12-HpETE that are of the A type (i.e. hepoxilin As, which contain an epoxy and alcohol residue separated from each other by a double (i.e. alkene) bond or, alternatively, B type (i.e. hepoxilin Bs, which contain epoxy and alcohol residues on adjacent carbons); these non-enxymatically formed products are a mixture of hydroxy and epoxy R,S stereoisomers and diastereomers.[11] In addition to arachidonic acid, ALOX12B metabolizes linoleic acid (LA) to 9(R)-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9R-HpODE):[11]

LA + O2 <math>\rightleftharpoons</math>9R-HpODE.

ALOXE3 is an atypical lipoxygenase in that under most but not all experimental conditions, it lacks the dioxygenase activity that converts PUFA to hydroperoxide metabolites; rather, it possess hepoxilin synthase (i.e. hydroperoxy isomerase) activity; that is, it converts hydroperoxy-containing PUFAs to hepoxilin-like epoxyalcohol products; these products, unlike those formed by non-enzymatic transformations, are specific isomers with just one form of the chiral hydroxy and epoxy residues. ALOX3E metabolizes 12R-HpETE to 8R-hydroxy-11R,12R-epoxy-eicosatrienoic acid[11] and metabolizes 9R-HpODE to products that contain either an epoxyalcohol or a ketone residue.[6][12] It exhibits relatively weak activity in conducting this conversion on free 9R-HODE but stronger activity when 9R-HpODE is presented as its methyl ester. ALOXE3's primary function in epidermal tissue appears to be to metabolize the 9R-HpODE moiety that is not free but rather esterified to certain ceramide lipids.

LA is the most abundant fatty acid in the skin epidermis, being present mainly esterified to the omega-hydroxyl residue of amide-linked omega-hydroxylated very long chain fatty acids (VLCFAs) in a unique class of ceramides termed esterified omega-hydroxyacyl-sphingosine (EOS). EOS is an intermediate component in a proposed multi-step metabolic pathway which delivers VLCFAs to the cornified lipid envelop in the skin's Stratum corneum; the presence of these wax-like, hydrophobic VLCFAs is needed to maintain the skin's integrity and functionality as a water barrier (see Lung microbiome#Role of the epithelial barrier).[6] ALOX12B metabolizes the LA in EOS to its 9R-hydroperoxy derivative which ALOXE3 then converts to three ceramide-esterified products: a) 9R,10R-trans-epoxide,13R-hydroxy-10E-octadecenoic acid, b) 9-keto-10E,12Z-octadecadienoic acid, and c) 9R,10R-trans-epoxy-13-keto-11E-octadecenoic acid.[6][12] The ALOX12B/ALOE3-oxidized products, it is proposed, signal for their hydrolysis (i.e. removal) from EOS; this allows the multi-step metabolic pathway to proceed in delivering the VLCFAs to the cornified lipid envelop in the skin's Stratum corneum.[6][13]

Other tissues

AloxE3 appears responsible for forming hepoxilins A and/or B from 12R-HpETE in the spinal fluids of rats[14] and ALOXE3 is proposed to be responsible for the formation of these hepoxilins in various human tissues[11][15] although the presence and activity of ALOXE3 in many of these hepoxilin-forming tissues has not yet been demonstrated.

Spinal Aloxe3, apparently through its ability to make hepoxilins, appears responsible for the hyperalgesia which accompanies inflammation in rats.[14]

Aloxe3 appears necessary and sufficient for the differentiation of mouse 3T3-L1 fibroblast cells into adipocytes (i.e. fat cells); the function of Aloxe3 in this differentiation appears to be to its metabolism 12R-HpETE into hepoxilins A3 or B3 which directly activate(s) Peroxisome proliferator-activated receptor gamma which in turn initiates the expression of adipocyte-differentiation genes.[16]

Clinical significance

Congenital ichthyosiform erythrodema

Deletions of Alox12b or Aloxe3 genes by gene knockout in mice cause a congenital scaly skin disease which is characterized by a greatly reduced skin water barrier function and other features found in the autosomal recessive nonbullous Congenital ichthyosiform erythroderma (ARCI) disease of humans.;[12] homoxzygous recessive deleterious mutations in ALOXE3 or ALOX12B are likewise causes, albeit rare, of this congenital disease in humans.[17][18] ARCI refers to nonsyndromic (i.e. not associated with other signs or symptoms) congenital Ichthyosis including Harlequin-type ichthyosis, Lamellar ichthyosis, and Congenital ichthyosiform erythroderma.[6] ARCI has an incidence of about 1/200,000 in European and North American populations; 40 different mutations in ALOX12B and 13 different mutations in ALOXE3 genes account for a total of about 10% of ARCI cases; these mutations are homoxygous recessive (see Dominance (genetics)), cause a total loss of ALOX12B or ALOXE3 function (see mutations), and can be associated with any of the three cited forms of the disease.[6][19]

Hepoxilin synthase

In mice lacking Aloxe3 activity due to gene knockout of the Alox3 gene, levels in skin of hepoxilins A3 and B3, as well as their metabolites, trioxilins A3 and B3, are greatly reduced.[11][20] Furthermore, rat Aloxe3 has been implicated in the production of hepoxilin B3 in studies that transfected its gene into cultured HEK 293 cells and similarly implicated in the inflammation-induced production of hepoxilin B3 in the spine of rats as well as the perception of pain (i.e. allodynia) by these animals using pharmacological inhibitor and siRNA-based gene knockdown studies.[14] Finally, cultured human skin cells, which are rich in ALOXE3 readily convert arachidonic acid as well as 12S-hydroperoxy-eicosatetraenoic acid to Hepoxilin B3; this production, in keeping with the higher content of ALOXE3, is far greater in the skin cells isolated from subjects with psoriasis.[6][11] These results suggest that ALOXE3 and its orthologs contribute greatly to or are the hepoxylin synthase activity responsible for producing bioactive hepoxilins (see hepoxilin) in the skin and other ALOXE3/ortholog-rich tissues of mammals, possibly including humans.

Other possible clinical significances

The distribution of ALOXE3 and Aloxe3 (see Tissue distribution, above) suggests that these lipoxygenases may serve functions not only in the skin but also in other tissues. The studies reported in the above "Activities, Other tissues", subsection allow that the pain perception and adipocyte differentiation activities of Aloxe3 in rodents might also occur in humans.

Toxicity

Interuterine delivery of e-Lox-3 to mice at gestational day 14.5 resulted in fetal growth restriction and intrauterine death apparently due to a strongly negative effect on placental development.

References

  1. 1.0 1.1 "Entrez Gene: ALOXE3 arachidonate lipoxygenase 3".
  2. Schneider C, Brash AR (August 2002). "Lipoxygenase-catalyzed formation of R-configuration hydroperoxides". Prostaglandins & Other Lipid Mediators. 68-69: 291–301. doi:10.1016/s0090-6980(02)00041-2. PMID 12432924.
  3. Panigrahy D, Kaipainen A, Greene ER, Huang S (December 2010). "Cytochrome P450-derived eicosanoids: the neglected pathway in cancer". Cancer Metastasis Reviews. 29 (4): 723–35. doi:10.1007/s10555-010-9264-x. PMC 2962793. PMID 20941528.
  4. Bylund J, Kunz T, Valmsen K, Oliw EH (January 1998). "Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 51–60. PMID 9435160.
  5. Buczynski MW, Dumlao DS, Dennis EA (June 2009). "Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology". Journal of Lipid Research. 50 (6): 1015–38. doi:10.1194/jlr.R900004-JLR200. PMC 2681385. PMID 19244215.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 Krieg P, Fürstenberger G (March 2014). "The role of lipoxygenases in epidermis". Biochimica et Biophysica Acta. 1841 (3): 390–400. doi:10.1016/j.bbalip.2013.08.005. PMID 23954555.
  7. Krieg P, Marks F, Fürstenberger G (May 2001). "A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression". Genomics. 73 (3): 323–30. doi:10.1006/geno.2001.6519. PMID 11350124.
  8. Boeglin WE, Kim RB, Brash AR (June 1998). "A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression". Proceedings of the National Academy of Sciences of the United States of America. 95 (12): 6744–9. doi:10.1073/pnas.95.12.6744. PMC 22619. PMID 9618483.
  9. Sun D, McDonnell M, Chen XS, Lakkis MM, Li H, Isaacs SN, Elsea SH, Patel PI, Funk CD (December 1998). "Human 12(R)-lipoxygenase and the mouse ortholog. Molecular cloning, expression, and gene chromosomal assignment". The Journal of Biological Chemistry. 273 (50): 33540–7. doi:10.1074/jbc.273.50.33540. PMID 9837935.
  10. Gardner HW (1989). "Oxygen radical chemistry of polyunsaturated fatty acids". Free Radical Biology & Medicine. 7 (1): 65–86. doi:10.1016/0891-5849(89)90102-0. PMID 2666279.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 Muñoz-Garcia A, Thomas CP, Keeney DS, Zheng Y, Brash AR (March 2014). "The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier". Biochimica et Biophysica Acta. 1841 (3): 401–8. doi:10.1016/j.bbalip.2013.08.020. PMC 4116325. PMID 24021977.
  12. 12.0 12.1 12.2 Zheng Y, Yin H, Boeglin WE, Elias PM, Crumrine D, Beier DR, Brash AR (July 2011). "Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope". The Journal of Biological Chemistry. 286 (27): 24046–56. doi:10.1074/jbc.M111.251496. PMC 3129186. PMID 21558561.
  13. Kuhn H, Banthiya S, van Leyen K (April 2015). "Mammalian lipoxygenases and their biological relevance". Biochimica et Biophysica Acta. 1851 (4): 308–30. doi:10.1016/j.bbalip.2014.10.002. PMC 4370320. PMID 25316652.
  14. 14.0 14.1 14.2 Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, Buczynski MW, Steinauer JJ, Fitzsimmons BL, Yaksh TL, Dennis EA (2013). "Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia". FASEB Journal. 27 (5): 1939–49. doi:10.1096/fj.12-217414. PMC 3633813. PMID 23382512.
  15. Pace-Asciak CR (2015). "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta. 1851 (4): 383–96. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838.
  16. Hallenborg P, Jørgensen C, Petersen RK, Feddersen S, Araujo P, Markt P, Langer T, Furstenberger G, Krieg P, Koppen A, Kalkhoven E, Madsen L, Kristiansen K (2010). "Epidermis-type lipoxygenase 3 regulates adipocyte differentiation and peroxisome proliferator-activated receptor gamma activity". Molecular and Cellular Biology. 30 (16): 4077–91. doi:10.1128/MCB.01806-08. PMC 2916447. PMID 20530198.
  17. Jobard F, Lefèvre C, Karaduman A, Blanchet-Bardon C, Emre S, Weissenbach J, Ozgüc M, Lathrop M, Prud'homme JF, Fischer J (January 2002). "Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1". Human Molecular Genetics. 11 (1): 107–13. doi:10.1093/hmg/11.1.107. PMID 11773004.
  18. Eckl KM, Krieg P, Küster W, Traupe H, André F, Wittstruck N, Fürstenberger G, Hennies HC (October 2005). "Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis". Human Mutation. 26 (4): 351–61. doi:10.1002/humu.20236. PMID 16116617.
  19. Sugiura K, Akiyama M (2015). "Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis". Journal of Dermatological Science. 79 (1): 4–9. doi:10.1016/j.jdermsci.2015.04.009. PMID 25982146.
  20. Krieg P, Rosenberger S, de Juanes S, Latzko S, Hou J, Dick A, Kloz U, van der Hoeven F, Hausser I, Esposito I, Rauh M, Schneider H (2013). "Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation". The Journal of Investigative Dermatology. 133 (1): 172–80. doi:10.1038/jid.2012.250. PMID 22832496.

External links

Further reading

  • Yu Z, Schneider C, Boeglin WE, Brash AR (June 2007). "Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha". Lipids. 42 (6): 491–7. doi:10.1007/s11745-007-3054-4. PMID 17436029.
  • Lesueur F, Bouadjar B, Lefèvre C, Jobard F, Audebert S, Lakhdar H, Martin L, Tadini G, Karaduman A, Emre S, Saker S, Lathrop M, Fischer J (April 2007). "Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13". The Journal of Investigative Dermatology. 127 (4): 829–34. doi:10.1038/sj.jid.5700640. PMID 17139268.
  • Yu Z, Schneider C, Boeglin WE, Brash AR (November 2006). "Human and mouse eLOX3 have distinct substrate specificities: implications for their linkage with lipoxygenases in skin". Archives of Biochemistry and Biophysics. 455 (2): 188–96. doi:10.1016/j.abb.2006.09.002. PMC 2636205. PMID 17045234.
  • Yu Z, Schneider C, Boeglin WE, Brash AR (January 2005). "Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3". Biochimica et Biophysica Acta. 1686 (3): 238–47. doi:10.1016/j.bbalip.2004.10.007. PMID 15629692.
  • Jobard F, Lefèvre C, Karaduman A, Blanchet-Bardon C, Emre S, Weissenbach J, Ozgüc M, Lathrop M, Prud'homme JF, Fischer J (January 2002). "Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1". Human Molecular Genetics. 11 (1): 107–13. doi:10.1093/hmg/11.1.107. PMID 11773004.
  • Krieg P, Marks F, Fürstenberger G (May 2001). "A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression". Genomics. 73 (3): 323–30. doi:10.1006/geno.2001.6519. PMID 11350124.