ALOX15

Description

The ALOX15 (arachidonate 15-lipoxygenase) is a protein-coding gene located on chromosome 17.

ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically important products. ▼ Gene Function Kelavkar and Badr (1999) stated that the ALOX15 gene product is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. Kelavkar and Badr (1999) described experiments yielding data that supported the hypothesis that loss of the TP53 gene, or gain-of-function activities resulting from the expression of its mutant forms, regulates ALOX15 promoter activity in human and in mouse, albeit in directionally opposite manners. These studies defined a direct link between ALOX15 gene activity and an established tumor-suppressor gene located in close chromosomal proximity. Kelavkar and Badr (1999) referred to this as evidence that 15-lipoxygenase is a mutator gene. ▼ Mapping By PCR analysis of a human-hamster somatic hybrid DNA panel, Funk et al. (1992) demonstrated that genes for 12-lipoxygenase and 15-lipoxygenase are located on human chromosome 17, whereas the most unrelated lipoxygenase (5-lipoxygenase) was mapped to chromosome 10. Kelavkar and Badr (1999) stated that the ALOX15 gene maps to 17p13.3 in close proximity to the tumor-suppressor gene TP53 (191170). In humans, it is encoded by the ALOX15 gene located on chromosome 17p13.3. This 11 kilobase pair gene consists of 14 exons and 13 introns coding for a 75 kilodalton protein composed of 662 amino acids.

ALOX15 is a non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids, generating a spectrum of bioactive lipid mediators. It inserts peroxyl groups at C12 or C15 of arachidonate, producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE. It can then act on 12-HPETE to produce hepoxilins, which may show pro-inflammatory properties. ALOX15 can also peroxidize linoleate to 13-hydroperoxyoctadecadienoate/13-HPODE. It may participate in the sequential oxidations of DHA to generate specialized pro-resolving mediators (SPMs) like resolvin D5 and (7S,14S)-diHPDHA, which actively down-regulate the immune response and have anti-aggregation properties with platelets. ALOX15 can convert epoxy fatty acids to hydroperoxy-epoxides derivatives, followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides. This enzyme plays an important role in maintaining self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine, which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, ALOX15 may play a role in epithelial wound healing in the cornea through the production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization, which is crucial for several biological processes such as the phagocytosis of apoptotic cells. ALOX15 is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver. Finally, ALOX15 is also involved in the cellular response to IL13/interleukin-13. It interacts with PEBP1; in response to IL13/interleukin-13, prevents the interaction of PEBP1 with RAF1 to activate the ERK signaling cascade.

ALOX15 is also known as 12-LOX, 15-LOX, 15-LOX-1, LOG15.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing