View source for ALOX12B

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Arachidonate 12-lipoxygenase, 12R type''', also known as '''ALOX12B''', '''12''R''-LOX''', and '''arachidonate lipoxygenase 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}}</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 | doi-access = free }}</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 | doi-access = free }}</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 | 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 = 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  |doi-access=free }}</ref>

==Activity==
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:

{{center|
arachidonic acid + O<sub>2</sub> <math>\rightleftharpoons</math> 12''R''-HpETE → 12''R''-HETE
}}

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 (BBA) - Molecular and Cell Biology of Lipids | 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 + O<sub>2</sub> <math>\rightleftharpoons</math> 9''R''-HpODE → 9''R''-HODE
}}

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 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"/> 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 (BBA) - Molecular and Cell Biology of Lipids | 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 and thyroid glands, pancreas, brain, and plasma blood leukocytes.<ref name="Schneider_2002"/>

==Clinical significance==

===Congenital ichthyosiform erythrodema===
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.{{citation needed|date=October 2020}}  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.{{citation needed|date=October 2020}} 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 (BBA) - Molecular and Cell Biology of Lipids | 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 [[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"/> 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  |doi-access=free }}</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 | s2cid = 4012229 }}
* {{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 | doi-access = free | url = https://www.openaccessrepository.it/record/148226/files/fulltext.pdf }}
* {{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 (BBA) - Molecular and Cell Biology of Lipids | volume = 1686 | issue = 3 | pages = 238–47 | date = January 2005 | pmid = 15629692 | doi = 10.1016/j.bbalip.2004.10.007 }}
* {{cite book | vauthors = McDonnell M, Li H, Funk CD | title = Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5 | chapter = Characterization of Epidermal 12(S) and 12(R) Lipoxygenases | series = Advances in Experimental Medicine and Biology | date = 2002 | volume = 507 | pages = 147–53 | pmid = 12664578 | doi = 10.1007/978-1-4615-0193-0_23 | isbn = 978-1-4613-4960-0 }}
* {{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 | doi-access = free }}
{{Refend}}

==External links==
* {{UCSC gene info|ALOX12B}}

[[Category:Fatty acids]]