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ALOX12

Official Full Name
arachidonate 12-lipoxygenase, 12S type
Organism
Homo sapiens
GeneID
239
Background
This gene encodes a member of the lipoxygenase family of proteins. The encoded enzyme acts on different polyunsaturated fatty acid substrates to generate bioactive lipid mediators including eicosanoids and lipoxins. The encoded enzyme and its reaction products have been shown to regulate platelet function. Elevated expression of this gene has been observed in pancreatic islets derived from human diabetes patients. Allelic variants in this gene may be associated with susceptibility to toxoplasmosis. Multiple pseudogenes of this gene have been identified in the human genome. [provided by RefSeq, Aug 2017]
Synonyms
LOG12; 12-LOX; 12S-LOX;
Bio Chemical Class
Oxygenase
Protein Sequence
MGRYRIRVATGAWLFSGSYNRVQLWLVGTRGEAELELQLRPARGEEEEFDHDVAEDLGLLQFVRLRKHHWLVDDAWFCDRITVQGPGACAEVAFPCYRWVQGEDILSLPEGTARLPGDNALDMFQKHREKELKDRQQIYCWATWKEGLPLTIAADRKDDLPPNMRFHEEKRLDFEWTLKAGALEMALKRVYTLLSSWNCLEDFDQIFWGQKSALAEKVRQCWQDDELFSYQFLNGANPMLLRRSTSLPSRLVLPSGMEELQAQLEKELQNGSLFEADFILLDGIPANVIRGEKQYLAAPLVMLKMEPNGKLQPMVIQIQPPNPSSPTPTLFLPSDPPLAWLLAKSWVRNSDFQLHEIQYHLLNTHLVAEVIAVATMRCLPGLHPIFKFLIPHIRYTMEINTRARTQLISDGGIFDKAVSTGGGGHVQLLRRAAAQLTYCSLCPPDDLADRGLLGLPGALYAHDALRLWEIIARYVEGIVHLFYQRDDIVKGDPELQAWCREITEVGLCQAQDRGFPVSFQSQSQLCHFLTMCVFTCTAQHAAINQGQLDWYAWVPNAPCTMRMPPPTTKEDVTMATVMGSLPDVRQACLQMAISWHLSRRQPDMVPLGHHKEKYFSGPKPKAVLNQFRTDLEKLEKEITARNEQLDWPYEYLKPSCIENSVTI
Open
Approved Drug
0
Clinical Trial Drug
0
Discontinued Drug
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Detailed Information

The ALOX12 gene genes for arachidonate 12-lipoxygenase, a prominent member of the lipoxygenase family that is essential to the metabolism of polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA). Important for several physiological activities, including inflammation control and platelet function, eicosanoids and lipoxins are produced by ALOX12 by helping molecular oxygen to be incorporated into AA. ALOX12's impact on many metabolic pathways makes it a major player in many illnesses, including cancer, vascular diseases, diabetes, and neurological disorders.

Mechanisms of ALOX12 in Lipid Metabolism ALOX12 catalyzes the synthesis of lipid hydroperoxides, especially 12-hydroperoxy eicosatetraenoic acid (12S-HPETE), hence regulating immunological response and platelet activation. ALOX12 also encourages the epoxidation of double bonds in PUFAs, therefore producing specific pro-resolving mediators (SPMs) that serve to downregulate inflammation and encourage tissue repair. Furthermore, ALOX12 modulates integrin beta-1 expression and pathways linked to vascular endothelial growth factor (VEGF), therefore fostering an environment fit for cancer cell survival and proliferation.

ALOX12 Biochemical Features

Gaining an understanding of ALOX12's molecular properties helps one to appreciate its function in both health and illness. Comprising 14 exons and 13 introns, the human ALOX12 gene is found at 17p13.1 spanning 15 kb. Its regulatory components suggest that ALOX12 is not acting as a housekeeping gene but rather responds to different physiological events. ALOX12 expression and function are substantially influenced by genetic variances including methylation and environmental oxidative stress.

Expressing in many cell types, including immune cells and platelets, ALOX12 contains three isoforms that help to explain its physiological functions. Especially interesting is the platelet type ALOX12 as it combines with secreted phospholipase A2 to generate 12(S)-HETE, a vital component in inflammation and cell signaling.

ALOX12 and oxidative stress

Oxidative stress (OS), brought on by an imbalance between oxidative and antioxidant actions, fuels many illnesses and aging. Studies show that in skin fibroblasts treated with antioxidants such as vitamin C and cancer cells devoid of mitochondrial DNA, ALOX12 expression is elevated. Moreover, ALOX12 variations are connected to neurodegenerative diseases such as post-traumatic stress disorder (PTSD), therefore highlighting the importance of the gene in oxidative stress-related disorders.

Studies reveal that by raising reactive oxygen species (ROS) levels, ALOX12 and related compounds might aggravate oxidative stress. For example, ALOX12 helps pancreatic β-cells produce ROS, which causes malfunction and cell death. The interaction between ALOX12 and NADPH oxidase pathways greatly affects cellular oxidative state, therefore underscoring the enzyme's dual function in lipid metabolism and oxidative stress.

Figure 1 depicts the involvement of ALOX12 in oxidative stress and inflammation, showcasing key molecular players and pathways that it influences.Figure 1. The Role of ALOX12 in Oxidative Stress (A) and Inflammation (B). (Zheng Z, et al., 2020)

ALOX12 and Inflammation

Production of lipoxins and improvement of human defense against bacterial infections depend on ALOX12. Its expression is raised in many inflammatory diseases, including cavitary TB; it is correlated favorably with bacterial load and neutrophil numbers. This link shows how important ALOX12 is for moderating inflammatory reactions.

Products of the enzyme, especially 12-HETE, affect immune cell recruitment to areas of inflammation using macrophage polarization and cytokine regulation, therefore fostering resolution. Still, too much ALOX12 activity may aggravate inflammation, which fuels conditions like chronic obstructive pulmonary disease and arthritis.

Alox 12 and Cancer

Studies show ALOX12's involvement in prostate, breast, and colorectal as well as other malignancies. Through processes encouraging lipid production, cell proliferation, and inflammation, abnormal ALOX12 expression is associated with tumor growth. Increased risk of colorectal cancer is linked to genetic variations including rs11571339 and rs2073438, indicating a genetic predisposition shaped by lipid signaling pathways.

In response to chemotherapy, ALOX12 improves tumor cell survival in breast cancer. While downregulation improves treatment sensitivity, overexpression may prevent death. This paradox highlights ALOX12's multifarious role as a tumor promoter and possible treatment target. Its part in lipoxin generation also points to a complex effect on the tumor microenvironment and immune response.

Alox12 in Vascular Conditions

The activity of ALOX12 is intimately related to atherosclerosis and heart diseases. Variants like rs2271316 link with coronary artery calcification; ALOX12 expression in platelets affects coagulation and thrombosis. Especially 12S-HETE, the lipid mediators generated show chemotactic and proliferative effects on vascular smooth muscle cells, hence promoting vascular remodeling and damage responses.

ALOX12 activation produces 12S-HETE in ischemic conditions, which could help to prevent ischemia-reperfusion damage. Its expression in disorders including diabetes and hypertension points to ALOX12's potential as a therapeutic target for reducing vascular consequences.

ALOX12 and Diabetic Conditions

The link of ALOX12 with diabetes, especially type 1 (T1D) and type 2 (T2D), emphasizes its significance in metabolic diseases. Increased ALOX12 expression in pancreatic islets from diabetics suggests its participation in disease pathogenesis. ALOX12 might affect immune cell activity in the pancreas in T1D, hence fueling autoimmune processes.

In T2D, reducing ALOX12 shields pancreatic β-cells from oxidative stress and increases insulin production, suggesting that ALOX12 manipulation might have therapeutic effects. Emphasizing its more general influence on problems, its products also contribute to diabetic nephropathy and retinopathy.

ALOX12 in Neurological Conditions

The consequences of ALOX12 include neurological disorders; expression patterns connected to disorders such as bipolar illness and schizophrenia define these ailments. For children with Down syndrome, notable ALOX12 expression points to a function in neurodevelopmental processes. With the interaction between ALOX12, arachidonic acid metabolism, and inflammatory pathways providing an understanding of the pathogenesis of neurodegenerative diseases, its association with neuroinflammation and oxidative stress positions ALOX12 as a potential biomarker and therapeutic target.

References:

  1. Zheng Z, Li Y, Jin G, Huang T, et al. The biological role of arachidonic acid 12-lipoxygenase (ALOX12) in various human diseases. Biomed Pharmacother. 2020;129:110354.
  2. Mitsui T, Makino S, Tamiya G, et al. ALOX12 mutation in a family with dominantly inherited bleeding diathesis. J Hum Genet. 2021;66(8):753-759.
  3. Contursi A, Tacconelli S, Hofling U, et al. Biology and pharmacology of platelet-type 12-lipoxygenase in platelets, cancer cells, and their crosstalk. Biochem Pharmacol. 2022;205:115252.
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