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| {{Infobox_gene}} | | {{Short description|Enzyme encoded by the ALOX12B gene}} |
| '''Arachidonate 12-lipoxygenase, 12R type''', also known as '''ALOX12B''', '''12''R''-LOX''', and '''arachiconate lipoygenase 3''', is a [[lipoxygenase]]-type [[enzyme]] composed of 701 [[amino acids]] and encoded by the ''ALOX12B'' [[gene]].<ref name="entrez">{{Cite web| title = Entrez Gene: ALOX12B arachidonate 12-lipoxygenase, 12R type| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=242| accessdate = }}</ref><ref name="pmid9618483">{{cite journal | vauthors = Boeglin WE, Kim RB, Brash AR | title = A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 12 | pages = 6744–9 | date = June 1998 | pmid = 9618483 | pmc = 22619 | doi = 10.1073/pnas.95.12.6744 | bibcode = 1998PNAS...95.6744B }}</ref><ref name="pmid9837935">{{cite journal | vauthors = Sun D, McDonnell M, Chen XS, Lakkis MM, Li H, Isaacs SN, Elsea SH, Patel PI, Funk CD | title = Human 12(R)-lipoxygenase and the mouse ortholog. Molecular cloning, expression, and gene chromosomal assignment | journal = The Journal of Biological Chemistry | volume = 273 | issue = 50 | pages = 33540–7 | date = December 1998 | pmid = 9837935 | doi = 10.1074/jbc.273.50.33540 }}</ref><ref>https://www.wikigenes.org/e/gene/e/242.html</ref> The gene is located on [[chromosome 17]] at position 13.1 where it forms a cluster with two other lipoxygenases, [[ALOXE3]] and [[ALOX15B]].<ref name="Schneider_2002">{{cite journal | vauthors = Schneider C, Brash AR | title = Lipoxygenase-catalyzed formation of R-configuration hydroperoxides | journal = Prostaglandins & Other Lipid Mediators | volume = 68–69 | issue = | pages = 291–301 | date = August 2002 | pmid = 12432924 | doi = 10.1016/s0090-6980(02)00041-2 }}</ref> Among the human lipoxygenases, ALOX12B is most closely (54% identity) related in amino acid sequence to [[ALOXE3]]<ref>{{cite journal | vauthors = Klein A, Pappas SC, Gordon P, Wong A, Kellen J, Kolin A, Robinson JB, Malkin A | title = The effect of nonviral liver damage on the T-lymphocyte helper/suppressor ratio | journal = Clinical Immunology and Immunopathology | volume = 46 | issue = 2 | pages = 214–20 | date = February 1988 | pmid = 2962793 | doi = 10.1016/0090-1229(88)90184-5 }}</ref><ref name="ReferenceC">{{cite journal | vauthors = Bylund J, Kunz T, Valmsen K, Oliw EH | title = Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 284 | issue = 1 | pages = 51–60 | date = January 1998 | pmid = 9435160 }}</ref><ref>{{cite journal | vauthors = Buczynski MW, Dumlao DS, Dennis EA | title = Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology | journal = Journal of Lipid Research | volume = 50 | issue = 6 | pages = 1015–38 | date = June 2009 | pmid = 19244215| pmc = 2681385 | doi = 10.1194/jlr.R900004-JLR200 }}</ref>
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| ==Activity==
| | '''ALOX12B''' is an enzyme that in humans is encoded by the '''ALOX12B''' gene. This enzyme is a member of the [[lipoxygenase]] family, which is involved in the metabolism of [[polyunsaturated fatty acids]] to produce [[bioactive lipid mediators]]. |
| ALOX12B [[oxygenates]] [[arachidonic acid]] by adding molecular oxygen (O<sub>2</sub>) in the form of a [[hydroperoxyl]] (HO<sub>2</sub>) [[residue]] to its 12th carbon thereby forming 12(''R'')-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-icosatetraenoic acid (also termed 12(''R'')-HpETE or 12''R''-HpETE).<ref name="pmid9618483" /><ref name="pmid9837935" /> When formed in cells, 12''R''-HpETE may be quickly reduced to its [[hydroxyl]] analog (OH), 12(''R'')-hydroxy-5'''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid (also termed 12(''R'')-HETE or 12''R''-HETE), by ubiquitous [[peroxidase]]-type enzymes. These sequential [[metabolic]] reactions are:
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| <center>
| | ==Function== |
| arachidonic acid + O<sub>2</sub> 12''R''-HpETE → 12''R''-HETE
| | ALOX12B is primarily expressed in the [[epidermis]] and plays a crucial role in the formation of the skin barrier. It catalyzes the oxygenation of [[arachidonic acid]] and other polyunsaturated fatty acids to produce [[hydroperoxyeicosatetraenoic acids]] (HPETEs), which are further converted into [[hydroxyeicosatetraenoic acids]] (HETEs). These metabolites are involved in the regulation of [[inflammation]], [[cell proliferation]], and [[differentiation]]. |
| </center>
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| 12''R''-HETE stimulates animal and human [[neutrophil]] [[chemotaxis]] and other responses in vitro and is able to elicit [[inflammatory]] responses when injected into the skin of an animal model<ref name="pmid7803484">{{cite journal | vauthors = O'Flaherty JT, Cordes JF, Lee SL, Samuel M, Thomas MJ | title = Chemical and biological characterization of oxo-eicosatetraenoic acids | journal = Biochimica et Biophysica Acta | volume = 1201 | issue = 3 | pages = 505–15 | date = December 1994 | pmid = 7803484 | doi = 10.1016/0304-4165(94)90083-3 }}</ref><ref name="pmid7601505">{{cite journal | vauthors = Fretland DJ, Anglin CP, Bremer M, Isakson P, Widomski DL, Paulson SK, Docter SH, Djuric SW, Penning TD, Yu S | title = Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228: impact upon leukotriene B4- and 12(R)-HETE-mediated events | journal = Inflammation | volume = 19 | issue = 2 | pages = 193–205 | date = April 1995 | pmid = 7601505 | doi = 10.1007/bf01534461 }}</ref> However, the production of 12''R''-HETE for this or other purposes may not be primary function of ALOX12B.
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| ALOX12B is also capable of metabolizing free [[linoleic acid]] to 9(''R'')-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9''R''-HpODE) which is also rapidly converted to its hydroxyl derivative, 9-Hydroxyoctadecadienoic acid (9''R''-HODE).<ref name="pmid24021977">{{cite journal | vauthors = Muñoz-Garcia A, Thomas CP, Keeney DS, Zheng Y, Brash AR | title = The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier | journal = Biochimica et Biophysica Acta | volume = 1841 | issue = 3 | pages = 401–8 | date = March 2014 | pmid = 24021977 | pmc = 4116325 | doi = 10.1016/j.bbalip.2013.08.020 }}</ref> | |
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| <center>
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| Linoleic acid + O<sub>2</sub> 9''R''-HpODE → 9''R''-HODE
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| </center>
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| The ''S'' [[stereoisomer]] of 9''R''-HODE, 9''S''-HODE, has a range of [[biological]] activities related to [[oxidative stress]] and pain perception (see [[9-Hydroxyoctadecadienoic acid]]. It is known or likely that 9''R''-HODE possesses at least some of these activities. For example, 9''R''-HODE, similar to 9''S''-HODE, mediates the perception of acute and chronic pain induced by heat, UV light, and inflammation in the skin of [[Rodent|rodents]] (see [[9-Hydroxyoctadecadienoic acid#9-HODEs as mediators of pain perception]]). However, production of these LA metabolites does not appear to be the primary function of ALOX12B; ALOX12B's primary function appears to be to metabolize linoleic acid that is not free but rather esterified to certain {{citation needed|date=July 2017}}
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| ===Proposed principal activity of ALOX12B===
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| ALOX12B targets [[Linoleic acid]] (LA). 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 acid]]s (VLCFAs) in a unique class of [[ceramide]]s 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]]).<ref name="Krieg_2014" /> ALOX12B metabolizes the LA in EOS to its 9-hydroperoxy derivative; ALOXE3 then converts this derivative to three products: '''a)''' 9''R'',10''R''-trans-[[epoxide]],13''R''-hydroxy-10''E''-octadecenoic acid, '''b)''' 9-keto-10''E'',12''Z''-octadecadienoic acid, and '''c)''' 9''R'',10''R''-trans-epoxy-13-keto-11''E''-octadecenoic acid.<ref name="Krieg_2014" /><ref name="Zheng_2011">{{cite journal | vauthors = Zheng Y, Yin H, Boeglin WE, Elias PM, Crumrine D, Beier DR, Brash AR | title = 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 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 27 | pages = 24046–56 | date = July 2011 | pmid = 21558561 | pmc = 3129186 | doi = 10.1074/jbc.M111.251496 }}</ref> These ALOX12B-oxidized products signal for the [[hydrolysis]] (i.e. removal) of the oxidized products 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.<ref name="Krieg_2014" /><ref name="pmid25316652">{{cite journal | vauthors = Kuhn H, Banthiya S, van Leyen K | title = Mammalian lipoxygenases and their biological relevance | journal = Biochimica et Biophysica Acta | volume = 1851 | issue = 4 | pages = 308–30 | date = April 2015 | pmid = 25316652 | pmc = 4370320 | doi = 10.1016/j.bbalip.2014.10.002 }}</ref>
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| ==Tissue distribution==
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| ALOX12B protein has been detected in humans that in the same tissues the express ALOXE3 and ALOX15B viz., upper layers of the human skin and tongue and in tonsils.<ref name="Schneider_2002" /> mRNA for it has been detected in additional tissues such as the [[lung]], [[testis]], [[adrenal gland]], [[ovary]], [[prostate]], and skin with lower abundance levels detected in [[Salivary gland|salivary]] and [[Thyroid gland|thyroid glands]], [[pancreas]], [[brain]], and plasma blood [[leukocytes]].<ref name="Schneider_2002" />
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| ==Clinical significance== | | ==Clinical significance== |
| | Mutations in the ALOX12B gene have been associated with a rare genetic disorder known as [[autosomal recessive congenital ichthyosis]] (ARCI). This condition is characterized by abnormal skin scaling over the entire body due to defects in the skin barrier function. The ALOX12B mutations lead to a deficiency in the production of specific lipid mediators necessary for normal skin barrier formation. |
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| ===Congenital ichthyosiform erythrodema=== | | ==Pathway== |
| [[Deletion|Deletions]] of ''Alox12b'' or ''AloxE2'' genes in mice cause a [[congenital]] scaly skin disease which is characterized by a greatly reduced skin water barrier function and is similar in other ways to the [[autosomal recessive]] nonbullous [[Congenital ichthyosiform erythroderma]] (ARCI) disease of humans.<ref name="Zheng_2011" /> Mutations in many of the genes that encode proteins, including ALOX12B and ALOXE3, which conduct the steps that bring and then bind VLCFA to the stratums [[corneum]] are associated with ARCI.<ref name="pmid11773004">{{cite journal | vauthors = Jobard F, Lefèvre C, Karaduman A, Blanchet-Bardon C, Emre S, Weissenbach J, Ozgüc M, Lathrop M, Prud'homme JF, Fischer J | title = Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1 | journal = Human Molecular Genetics | volume = 11 | issue = 1 | pages = 107–13 | date = January 2002 | pmid = 11773004 | doi = 10.1093/hmg/11.1.107 }}</ref><ref name="pmid16116617">{{cite journal | vauthors = Eckl KM, Krieg P, Küster W, Traupe H, André F, Wittstruck N, Fürstenberger G, Hennies HC | title = Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis | journal = Human Mutation | volume = 26 | issue = 4 | pages = 351–61 | date = October 2005 | pmid = 16116617 | doi = 10.1002/humu.20236 }}</ref> 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]].<ref name="Krieg_2014">{{cite journal | vauthors = Krieg P, Fürstenberger G | title = The role of lipoxygenases in epidermis | journal = Biochimica et Biophysica Acta | volume = 1841 | issue = 3 | pages = 390–400 | date = March 2014 | pmid = 23954555 | doi = 10.1016/j.bbalip.2013.08.005 }}</ref> 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 case; these mutations uniformly cause a total loss of ALOX12B or ALOXE3 function (see [[Mutation|mutations]]).<ref name="Krieg_2014" />
| | ALOX12B is part of the [[lipoxygenase pathway]], which is one of the major pathways for the metabolism of arachidonic acid. This pathway involves the conversion of arachidonic acid into various eicosanoids, which are signaling molecules that exert complex control over many bodily systems, including the [[immune system]]. |
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| ===Proliferative skin diseases===
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| In [[psoriasis]] and other proliferative skin diseases such as the [[Erythroderma]]s underlying lung cancer, [[cutaneous T cell lymphoma]], and drug reactions, and in [[Discoid lupus]], [[Seborrheic dermatitis]], Subacute [[Cutaneous lupus erythematosus]], and [[Pemphigus foliaceus]], cutaneous levels of ALOX12B [[mRNA]] and 12''R''-HETE are greatly increased.<ref name="Schneider_2002" /><ref name="pmid7829882">{{cite journal | vauthors = Baer AN, Klaus MV, Green FA | title = Epidermal fatty acid oxygenases are activated in non-psoriatic dermatoses | journal = The Journal of Investigative Dermatology | volume = 104 | issue = 2 | pages = 251–5 | date = February 1995 | pmid = 7829882 | doi = 10.1111/1523-1747.ep12612793 }}</ref> It is not clear if these increases contribute to the disease by, for example, 12''R''-HETE [[induction]] of inflammation, or are primarily a consequence of skin proliferation.<ref name="Krieg_2014" />
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| ===Embryogenesis===
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| The expression of Alox12b and Aloxe3 [[mRNA]] in mice parallels, and is proposed to be [[instrumental]] for, skin development in mice [[embryogenesis]]; the human [[ortholog]]s of these genes, i.e. ALOX12B and ALOXE3, may have a similar role in humans.<ref name="Krieg_2014" />
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| ===Essential fatty acid deficiency===
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| Severe dietary deficiency of polyunsaturated [[omega 6 fatty acid]]s leads to the [[essential fatty acid deficiency]] syndrome that is characterized by scaly skin and excessive water loss; in humans and animal models the syndrome is fully reversed by dietary omega 6 fatty acids, particularly linoleic acid.<ref name="pmid25339684">{{cite journal | vauthors = Spector AA, Kim HY | title = Discovery of essential fatty acids | journal = Journal of Lipid Research | volume = 56 | issue = 1 | pages = 11–21 | date = January 2015 | pmid = 25339684 | pmc = 4274059 | doi = 10.1194/jlr.R055095 }}</ref> It is proposed that this [[deficiency disease]] resembles and has a similar basis to Congenital ichthyosiform erythrodema; that is, it is at least in part due to a deficiency of linoleic acid and thereby in the EOS-based delivery of VLCFA to the stratum [[corneum]].<ref name="Krieg_2014" />
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| ==References==
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| {{Reflist|33em}}
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| ==Further reading==
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| {{Refbegin|33em}}
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| * {{cite journal | vauthors = Yu Z, Schneider C, Boeglin WE, Brash AR | title = Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha | journal = Lipids | volume = 42 | issue = 6 | pages = 491–7 | date = June 2007 | pmid = 17436029 | doi = 10.1007/s11745-007-3054-4 }}
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| * {{cite journal | vauthors = 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 | title = Novel mutations in ALOX12B in patients with autosomal recessive congenital ichthyosis and evidence for genetic heterogeneity on chromosome 17p13 | journal = The Journal of Investigative Dermatology | volume = 127 | issue = 4 | pages = 829–34 | date = April 2007 | pmid = 17139268 | doi = 10.1038/sj.jid.5700640 }}
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| * {{cite journal | vauthors = Yu Z, Schneider C, Boeglin WE, Brash AR | title = Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3 | journal = Biochimica et Biophysica Acta | volume = 1686 | issue = 3 | pages = 238–47 | date = January 2005 | pmid = 15629692 | doi = 10.1016/j.bbalip.2004.10.007 }}
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| * {{cite journal | vauthors = McDonnell M, Li H, Funk CD | title = Characterization of epidermal 12(S) and 12(R) lipoxygenases | journal = Advances in Experimental Medicine and Biology | volume = 507 | issue = | pages = 147–53 | year = 2003 | pmid = 12664578 | doi = 10.1007/978-1-4615-0193-0_23 | isbn = 978-1-4613-4960-0 | series = <!-- --> }}
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| * {{cite journal | vauthors = Schneider C, Keeney DS, Boeglin WE, Brash AR | title = Detection and cellular localization of 12R-lipoxygenase in human tonsils | journal = Archives of Biochemistry and Biophysics | volume = 386 | issue = 2 | pages = 268–74 | date = February 2001 | pmid = 11368351 | doi = 10.1006/abbi.2000.2217 }}
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| * {{cite journal | vauthors = Krieg P, Marks F, Fürstenberger G | title = A gene cluster encoding human epidermis-type lipoxygenases at chromosome 17p13.1: cloning, physical mapping, and expression | journal = Genomics | volume = 73 | issue = 3 | pages = 323–30 | date = May 2001 | pmid = 11350124 | doi = 10.1006/geno.2001.6519 }}
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| * {{cite journal | vauthors = Tang K, Finley RL, Nie D, Honn KV | title = Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening | journal = Biochemistry | volume = 39 | issue = 12 | pages = 3185–91 | date = March 2000 | pmid = 10727209 | doi = 10.1021/bi992664v }}
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| * {{cite journal | vauthors = Boeglin WE, Kim RB, Brash AR | title = A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 12 | pages = 6744–9 | date = June 1998 | pmid = 9618483 | pmc = 22619 | doi = 10.1073/pnas.95.12.6744 | bibcode = 1998PNAS...95.6744B }}
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| {{Refend}}
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| ==External links==
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| *{{UCSC gene info|ALOX12B}} | | ==Related pages== |
| | * [[Lipoxygenase]] |
| | * [[Arachidonic acid]] |
| | * [[Eicosanoid]] |
| | * [[Autosomal recessive congenital ichthyosis]] |
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| [[Category:Cell biology]] | | [[Category:Enzymes]] |
| [[Category:Metabolic pathways]] | | [[Category:Human proteins]] |
| [[Category:Fatty acids]] | | [[Category:Genes on human chromosome 17]] |
| [[Category:Cutaneous conditions]]
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| [[Category:Genodermatoses]]
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| [[Category:Rare diseases]]
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| [[Category:Autosomal recessive disorders]]
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Enzyme encoded by the ALOX12B gene
ALOX12B is an enzyme that in humans is encoded by the ALOX12B gene. This enzyme is a member of the lipoxygenase family, which is involved in the metabolism of polyunsaturated fatty acids to produce bioactive lipid mediators.
Function[edit]
ALOX12B is primarily expressed in the epidermis and plays a crucial role in the formation of the skin barrier. It catalyzes the oxygenation of arachidonic acid and other polyunsaturated fatty acids to produce hydroperoxyeicosatetraenoic acids (HPETEs), which are further converted into hydroxyeicosatetraenoic acids (HETEs). These metabolites are involved in the regulation of inflammation, cell proliferation, and differentiation.
Clinical significance[edit]
Mutations in the ALOX12B gene have been associated with a rare genetic disorder known as autosomal recessive congenital ichthyosis (ARCI). This condition is characterized by abnormal skin scaling over the entire body due to defects in the skin barrier function. The ALOX12B mutations lead to a deficiency in the production of specific lipid mediators necessary for normal skin barrier formation.
Pathway[edit]
ALOX12B is part of the lipoxygenase pathway, which is one of the major pathways for the metabolism of arachidonic acid. This pathway involves the conversion of arachidonic acid into various eicosanoids, which are signaling molecules that exert complex control over many bodily systems, including the immune system.
Related pages[edit]
