ALOX12

Arachidonate 12-lipoxygenase
Rendering based on PDB 2ABU​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2ABU​, 3D3L​
Identifiers
Symbols	ALOX12 ; 12-LOX; 12S-LOX; LOG12
External IDs	OMIM: 152391 MGI: 87998 HomoloGene: 560 ChEMBL: 3687 GeneCards: ALOX12 Gene
EC number	1.13.11.31
Gene ontology Molecular function • arachidonate 12-lipoxygenase activity • iron ion binding • protein binding • linoleate 13S-lipoxygenase activity • oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen • hepoxilin-epoxide hydrolase activity • hepoxilin A3 synthase activity Cellular component • cytoplasm • cytosol • membrane • sarcolemma • extracellular exosome Biological process • movement of cell or subcellular component • aging • positive regulation of cell proliferation • positive regulation of endothelial cell migration • positive regulation of gene expression • negative regulation of muscle cell apoptotic process • arachidonic acid metabolic process • lipoxygenase pathway • fatty acid oxidation • positive regulation of cell growth • positive regulation of cell migration • superoxide anion generation • negative regulation of apoptotic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • linoleic acid metabolic process • small molecule metabolic process • positive regulation of endothelial cell differentiation • positive regulation of angiogenesis • positive regulation of cell adhesion • positive regulation of vasodilation • positive regulation of smooth muscle cell proliferation • hepoxilin metabolic process • hepoxilin biosynthetic process • positive regulation of mitochondrial depolarization • establishment of skin barrier • cellular response to lipid • reactive oxygen species metabolic process • negative regulation of platelet aggregation • leukotriene A4 metabolic process • lipoxin metabolic process • lipoxin A4 biosynthetic process • lipoxin B4 biosynthetic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	239	11684
Ensembl	ENSG00000108839	ENSMUSG00000000320
UniProt	P18054	P39655
RefSeq (mRNA)	NM_000697	NM_007440
RefSeq (protein)	NP_000688	NP_031466
Location (UCSC)	Chr 17: 7 – 7.01 Mb	Chr 11: 70.24 – 70.26 Mb
PubMed search

ALOX12 (EC 1.13.11.31), also known as arachidonate 12-lipoxygenase, 12-lipoxygenase, 12S-Lipoxygenase, 12-LOX, and 12S-LOX is a lipoxygenase-type enzyme that in humans is encoded by the ALOX12 gene which is located along with other lipoyxgenases on chromosome 17p13.3.^[1][2] ALOX12 is 75 kilodalton protein composed of 663 amino acids.

Nomenclature

Other systematic names for ALOX12 include platelet-type 12-lipoxygenase, arachidonate:oxygen 12-oxidoreductase, Delta12-lipoxygenase, 12Delta-lipoxygenase, C-12 lipoxygenase, leukotriene A4 synthase, and LTA4 synthase.

Discovery

ALOX12, originally called arachidonate 12-lipoxygenase was first characterized by the Nobel Laureate, Bengt I. Samuelsson, and his colleague, Mats Hamberg, in 1974 and was the first mammalian lipoxygenase to be characterized.^[3]

Activity

arachidonate 12-lipoxygenase
Identifiers
EC number	1.13.11.31
CAS number	82391-43-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

ALOX12 participates in arachidonic acid metabolism by conducting the following chemical reaction wherein the two substrates of this enzyme are arachidonic acid (also termed arachidonate or chemically as 5Z,8Z,11Z,14Z-eicosatetraenoic acid) and O₂ (i.e. oxygen) and its product is 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-hydroperoxyeicosatetraenoic acid or 12S-HpETE):^[3][4]

arachidonate + O₂ $\rightleftharpoons$ 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid

In cells, 12SHpETE may be further metabolized by ALOXE3 or possibly other, as yet not fully identified, hepoxilin synthases or epoxide hydrolases to hepoxilins A3 and B3 or, alternatively, non-enzymatically convert to various hepoxilin isomers.^[5][6][7] Far more commonly, however, 12S-HpETE is rapidly reduced to its hydroxyl product by ubiquitous cellular peroxidase activities thereby forming 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid, i.e. 12-hydroxyeicosatetraenoic acid or 12S-HETE.

ALOX12 is distinguished from another lipoxygenase enzyme, ALOX12B which metabolizes arachidonate to the 12R stereoisomer of 12S-HpETE viz., 12R-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12R-HpETE).

Interactions

ALOX12 has been shown to interact with Keratin 5^[8] and LMNA.^[8]

References

1. Funk CD, Funk LB, FitzGerald GA, Samuelsson B (May 1992). "Characterization of human 12-lipoxygenase genes". Proceedings of the National Academy of Sciences of the United States of America 89 (9): 3962–6. doi:10.1073/pnas.89.9.3962. PMC 525611. PMID 1570320.
2. "Entrez Gene: ALOX12 arachidonate 12-lipoxygenase".
3. Hamberg M, Samuelsson B (September 1974). "Prostaglandin endoperoxides. Novel transformations of arachidonic acid in human platelets". Proceedings of the National Academy of Sciences of the United States of America 71 (9): 3400–4. doi:10.1073/pnas.71.9.3400. PMC 433780. PMID 4215079.
4. Nugteren DH (February 1975). "Arachidonate lipoxygenase in blood platelets". Biochimica et Biophysica Acta 380 (2): 299–307. doi:10.1016/0005-2760(75)90016-8. PMID 804329.
5. 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.
6. 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. PMID 24021977.
7. Pace-Asciak CR (April 2015). "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta 1851 (4): 383–96. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838.
8. Tang K, Finley RL, Nie D, Honn KV (March 2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry 39 (12): 3185–91. doi:10.1021/bi992664v. PMID 10727209.

Further reading

• Yoshimoto T, Arakawa T, Hada T, Yamamoto S, Takahashi E (December 1992). "Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene". The Journal of Biological Chemistry 267 (34): 24805–9. PMID 1447217.
• Izumi T, Hoshiko S, Rådmark O, Samuelsson B (October 1990). "Cloning of the cDNA for human 12-lipoxygenase". Proceedings of the National Academy of Sciences of the United States of America 87 (19): 7477–81. doi:10.1073/pnas.87.19.7477. PMC 54770. PMID 2217179.
• Yoshimoto T, Yamamoto Y, Arakawa T, Suzuki H, Yamamoto S, Yokoyama C, Tanabe T, Toh H (November 1990). "Molecular cloning and expression of human arachidonate 12-lipoxygenase". Biochemical and Biophysical Research Communications 172 (3): 1230–5. doi:10.1016/0006-291X(90)91580-L. PMID 2244907.
• Funk CD, Furci L, FitzGerald GA (August 1990). "Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase". Proceedings of the National Academy of Sciences of the United States of America 87 (15): 5638–42. doi:10.1073/pnas.87.15.5638. PMC 54382. PMID 2377602.
• Flatman S, Morgan A, McDonald-Gibson RG, Davey A, Jonas GE, Slater TF (May 1988). "12-Lipoxygenase activity in human uterine cervix". Prostaglandins, Leukotrienes, and Essential Fatty Acids 32 (2): 87–94. doi:10.1016/0952-3278(88)90101-9. PMID 3406043.
• Wong PY, Westlund P, Hamberg M, Granström E, Chao PH, Samuelsson B (August 1985). "15-Lipoxygenase in human platelets". The Journal of Biological Chemistry 260 (16): 9162–5. PMID 3926763.
• Nakamura M, Ueda N, Kishimoto K, Yoshimoto T, Yamamoto S, Ishimura K (March 1995). "Immunocytochemical localization of platelet-type arachidonate 12-lipoxygenase in mouse blood cells". The Journal of Histochemistry and Cytochemistry 43 (3): 237–44. doi:10.1177/43.3.7868854. PMID 7868854.
• Hussain H, Shornick LP, Shannon VR, Wilson JD, Funk CD, Pentland AP, Holtzman MJ (January 1994). "Epidermis contains platelet-type 12-lipoxygenase that is overexpressed in germinal layer keratinocytes in psoriasis". The American Journal of Physiology 266 (1 Pt 1): C243–53. PMID 8304420.
• Arora JK, Lysz TW, Zelenka PS (June 1996). "A role for 12(S)-HETE in the response of human lens epithelial cells to epidermal growth factor and insulin". Investigative Ophthalmology & Visual Science 37 (7): 1411–8. PMID 8641843.
• Hagmann W, Gao X, Timar J, Chen YQ, Strohmaier AR, Fahrenkopf C, Kagawa D, Lee M, Zacharek A, Honn KV (November 1996). "12-Lipoxygenase in A431 cells: genetic identity, modulation of expression, and intracellular localization". Experimental Cell Research 228 (2): 197–205. doi:10.1006/excr.1996.0317. PMID 8912711.
• Nakamura M, Yamamoto S, Ishimura K (May 1997). "Subcellular localization of arachidonate 12-lipoxygenase and morphological effect of its overexpression on murine keratinocytes". Cell and Tissue Research 288 (2): 327–34. doi:10.1007/s004410050818. PMID 9082968.
• Nigam S, Kumar GS, Sutherland M, Schewe T, Ikawa H, Yamasaki Y, Ueda N, Yamamoto S (September 1999). "Metabolic suppression of platelet-type 12-lipoxygenase in human uterine cervix with invasive carcinoma". International Journal of Cancer 82 (6): 827–31. doi:10.1002/(SICI)1097-0215(19990909)82:6<827::AID-IJC10>3.0.CO;2-Q. PMID 10446449.
• Tornhamre S, Elmqvist A, Lindgren JA (April 2000). "15-Lipoxygenation of leukotriene A(4). Studies Of 12- and 15-lipoxygenase efficiency to catalyze lipoxin formation". Biochimica et Biophysica Acta 1484 (2-3): 298–306. doi:10.1016/S1388-1981(00)00017-2. PMID 10760478.
• Chen BK, Tsai TY, Huang HS, Chen LC, Chang WC, Tsai SB, Chang WC (2003). "Functional role of extracellular signal-regulated kinase activation and c-Jun induction in phorbol ester-induced promoter activation of human 12(S)-lipoxygenase gene". Journal of Biomedical Science 9 (2): 156–65. doi:10.1159/000048212. PMID 11914583.
• Winer I, Normolle DP, Shureiqi I, Sondak VK, Johnson T, Su L, Brenner DE (October 2002). "Expression of 12-lipoxygenase as a biomarker for melanoma carcinogenesis". Melanoma Research 12 (5): 429–34. doi:10.1097/00008390-200209000-00003. PMID 12394183.
• Gu J, Wen Y, Mison A, Nadler JL (February 2003). "12-lipoxygenase pathway increases aldosterone production, 3',5'-cyclic adenosine monophosphate response element-binding protein phosphorylation, and p38 mitogen-activated protein kinase activation in H295R human adrenocortical cells". Endocrinology 144 (2): 534–43. doi:10.1210/en.2002-220580. PMID 12538614.
• Fridman C, Ojopi EP, Gregório SP, Ikenaga EH, Moreno DH, Demetrio FN, Guimarães PE, Vallada HP, Gattaz WF, Dias Neto E (February 2003). "Association of a new polymorphism in ALOX12 gene with bipolar disorder". European Archives of Psychiatry and Clinical Neuroscience 253 (1): 40–3. doi:10.1007/s00406-003-0404-y. PMID 12664313.