ALOX12
Ensembl | |||||||||
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| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 17: 7 – 7.01 Mb | Chr 11: 70.13 – 70.15 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
ALOX12 (
Nomenclature
| arachidonate 12-lipoxygenase | |||||||||
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ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Other
Human ALOX12 and ALOX15 along with rodent leukocyte-type Alox12 and Alox15 are commonly termed 12/15-lipoxygenases based on their ability to metabolize arachidonic acid to both 12(S)-HpETE and 15(S)-HpETE and to conduct this same metabolism on arachidonic acid that is
ALOX12 is also distinguished from arachidonate 12-lipoxygenase, 12R type (ALOX12B), which metabolizes arachidonic acid to the R
Discovery
ALOX12, originally called arachidonate 12-lipoxygenase, was first characterized by the Nobel Laureate,
Tissue distribution
Based predominantly on the presence of its
Enzyme activities
The control of ALOX12 activity appears to rest principally on the availability of its
- arachidonate + O2 → 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid
In cells, 12SHpETE may be further metabolized by ALOX12 itself, by ALOXE3 or possibly other, as yet not fully identified, hepoxilin syntheses to hepoxilin A3 (8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and B3 (10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid):[16][17][18]
- 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid → 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid + 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid
Hepoxilins can promote certain
- 12S-hydroperoxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid → 12S-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid
12S-HETE promotes inflammation responses, may be involved in the perception of
It metabolizes the omega-3 fatty acid, docosahexaenoic acid (DHA i.e., 4(Z),7(Z),10(Z),13(Z),16(Z),19(Z)-docosahexaenoic acid to 14(R)-hydroperoxy-4(Z),8(Z),10(Z),12(E),16(Z),19(Z)-docosahexaenoic acid)(i.e. 17-hydroperoxy-DHA)
Then, ALOX12 or an unidentified epoxidase-type enzyme may metabolize this intermediate to an epoxide, 13,14-epoxy-4(Z),7(Z),9(E),11(E),16(Z),19(Z)-docosahexaenoic acid (i.e. 13,14-e-maresin)
This is further metabolized to 7R,14S-dihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid (i.e. Maresin 1), by an unidentified epoxide hydrolase-type enzyme:
- DHA → 17-hydroperoxy-DHA → 13,14-e-maresin → Maresin-1
Maresin 1 has a set of activities that may oppose those of 12(S)-HETE and the hepoxilins; it is a member of a class of PUFA metabolites termed Specialized pro-resolution mediators (SPMs) which possess anti-inflammatory, pain-alleviating, and other defensive activities.[20] ALOX12 also acts on leukotriene A4 (LTA4) in a two cellular reaction termed transcellular metabolism: human neutrophils metabolize arachidonic acid to its 5,6-epoxide, LTA4, and releases this intermediate to nearby neutrophils which metabolize it to lipoxin A4 (5S,6R,15S-trihydroxy-7E,9E,11Z,13Z-eicosatetraenoic acid) and lipoxin B4 (5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid); both lipoxins are SPMs with many SPM-like activities (see lipoxin).[21] ALOX12 may also metabolize lesser amounts of DHA to secondary products including 17-hydroperoxy-DHA, 11-hydroperoxy-DHA, and 8,14-dihydroxy-DHA[20] ALOX12 may likewise metabolize 5(S)-HETE to 5S,12S-dihydroxyeicosatetraenoic acid (12,15-diHETE) and 15S-HETE to 14,15S-diETE.[14] While these compounds have not been thoroughly evaluated for bioactivity, 17-hydroperoxy-HDHA and the reduced product to which it is rapidly converted in cells, 17-hydroxy-HDHA, have been shown to inhibit the growth of cultured human prostate cancer cell by causing them to enter apoptosis.[22]
Animal studies
Studies on rodents lacking or made deficient in the leukocyte-type 12-lipoxygenase, Alox12 (which is most closely related to human ALOX15) implicate this enzyme in: a) preventing the development and complications of dietary-induced and/or genetically induced
Preclinical studies
Metabolic syndrome
The
Blood vessels
A selective but not totally specific inhibitor of ALOX12 reduced the growth response of cultured human
Alzheimer's disease
Patients with
Cancer
Studies in prostate cancer find that human prostate cancer cell lines in culture overexpress ALOX12, overproduce 12(S)-HETE, and respond to 12(S)-HETE by increasing their rate of proliferation, increasing their cell surface expression of
Platelet function
Although first identified in human platelets, the role of ALOX12 and its major metabolites, 12(S)-HpETE and 12(S)-HETE in platelet function remains controversial and unclear; it is possible that the ALOX12-12(S)-HETE metabolic pathway has dual functions in promoting or inhibiting platelet responses depending on the stimulating agent and response studied but that inhibiting ALOX12 may ultimately prove useful in inhibiting platelet-related blood clotting.[19]
Other associations
The ALOX12 gene has susceptibility alleles (rs6502997,[28] rs312462,[29] rs6502998,[30] and rs434473[31]) for the parasitic disease, human congenital toxoplasmosis.[13][32] Fetus bearer of these alleles thus suffer an increased susceptibility to this disease.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000108839 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000320 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 1570320.
- ^ "Entrez Gene: ALOX12 arachidonate 12-lipoxygenase".
- ^ PMID 9373619.
- ^ PMID 25803446.
- ^ PMID 20970452.
- ^ PMID 4215079.
- PMID 1127383.
- PMID 2244907.
- ^ PMID 25316652.
- ^ PMID 21838667.
- PMID 804329.
- PMID 23954555.
- PMID 24021977.
- ^ PMID 25240838.
- ^ PMID 24685839.
- ^ PMID 26546723.
- PMID 16005201.
- PMID 23029040.
- ^ PMID 25708815.
- ^ "rs2073438". NCBI dbSNP.
- PMID 16514435.
- S2CID 12659175.
- PMID 10727209.
- ^ "rs6502997". NCBI dbSNP.
- ^ "rs312462". NCBI dbSNP.
- ^ "rs6502998". NCBI dbSNP.
- ^ "rs434473". NCBI dbSNP.
- PMID 24686056.
External links
- Human ALOX12 genome location and ALOX12 gene details page in the UCSC Genome Browser.
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. PMID 2217179.
- 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. 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. 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. 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. 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. S2CID 23548308.
- 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. S2CID 22417409.
- Tornhamre S, Elmqvist A, Lindgren JA (April 2000). "15-Lipoxygenation of leukotriene A4: Studies of 12- and 15-lipoxygenase efficiency to catalyze lipoxin formation". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1484 (2–3): 298–306. 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. S2CID 46753449.
- 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. S2CID 27336312.
- 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. 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. S2CID 21064663.
