Prab: CSV import

2025-03-22T19:16:50Z

CSV import

Prab at 16:45, 22 March 2025

2025-03-22T16:45:39Z

← Older revision		Revision as of 16:45, 22 March 2025
Line 66:		Line 66:
	[[Category:Autosomal recessive disorders]]		[[Category:Autosomal recessive disorders]]
	{{No image}}		{{No image}}
	~~__NOINDEX__~~

Prab: CSV import

2025-03-17T02:54:34Z

CSV import

← Older revision		Revision as of 02:54, 17 March 2025
Line 66:		Line 66:
	[[Category:Autosomal recessive disorders]]		[[Category:Autosomal recessive disorders]]
	{{No image}}		{{No image}}
			__NOINDEX__

Prab: CSV import

2025-02-10T05:16:58Z

CSV import

← Older revision		Revision as of 05:16, 10 February 2025
Line 65:		Line 65:
	[[Category:Rare diseases]]		[[Category:Rare diseases]]
	[[Category:Autosomal recessive disorders]]		[[Category:Autosomal recessive disorders]]
			{{No image}}

Spt: Added internal links.

2020-11-29T17:02:16Z

Added internal links.

New page

{{Infobox_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>

==Activity==
ALOX12B [[oxygenates]] [[arachidonic acid]] by adding molecular oxygen (O2) in the form of a [[hydroperoxyl]] (HO2) [[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:

<center>
arachidonic acid + O2 12''R''-HpETE → 12''R''-HETE
</center>

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.

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>

<center>
Linoleic acid + O2 9''R''-HpODE → 9''R''-HODE
</center>

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}}

===Proposed principal activity of ALOX12B===
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>

==Tissue distribution==
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" />

==Clinical significance==

===Congenital ichthyosiform erythrodema===
[[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" />

===Proliferative skin diseases===
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" />

===Embryogenesis===
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" />

===Essential fatty acid deficiency===
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" />

==References==
{{Reflist|33em}}

==Further reading==
{{Refbegin|33em}}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 =  }}
* {{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 }}
* {{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 }}
* {{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 }}
* {{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 }}
{{Refend}}

==External links==

*{{UCSC gene info|ALOX12B}}

[[Category:Cell biology]]
[[Category:Metabolic pathways]]
[[Category:Fatty acids]]
[[Category:Cutaneous conditions]]
[[Category:Genodermatoses]]
[[Category:Rare diseases]]
[[Category:Autosomal recessive disorders]]

ALOX12B - Revision history

Prab: CSV import

Prab at 16:45, 22 March 2025

Prab: CSV import

Prab: CSV import

Spt: Added internal links.