Disease relevance of ALOX15

• Here we studied the association between bone mineral density and an ALOX15 gene single nucleotide polymorphism to assess the potential involvement of the human ALOX15 gene in postmenopausal osteoporosis [1].
• These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder [2].
• Further in vivo studies employing a rat carrageenan-induced paw edema model showed that the oxime compounds (17a, 18a) were more potent anti-inflammatory agents than the 5-LOX inhibitor caffeic acid, and 15-LOX inhibitor nordihydroguaiaretic acid (NDGA), but less potent than the selective COX-2 inhibitor celecoxib [3].
• Oxidative modification of low-density lipoprotein (LDL) has been implicated as a patho-physiological process in early atherogenesis and 15-lipoxygenases (15-LOX) may be involved [4].
• Examination of knockout and transgenic animals revealed important roles for 12/15-LOX in inflammatory diseases, including atherosclerosis, cancer, osteoporosis, angiotension II-dependent hypertension and diabetes [5].

Psychiatry related information on ALOX15

• The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls [6].
• These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD [6].

High impact information on ALOX15

• These data suggest that the arachidonate 15-lipoxygenase is of pathophysiological importance during the early stages of atherogenesis [7].
• NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15-LOX in neoplastic cells have been unknown [8].
• Immunocytochemical localization of arachidonate 15-lipoxygenase in erythrocytes, leukocytes, and airway cells [9].
• Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD [6].
• These and other LOX data led us to propose that the various LOX pathways exist in a dynamic balance that shifts during carcinogenesis toward 5-, 8-, and 12-LOX (and cyclooxygenase-2) and away from 15-LOX [10].

Biological context of ALOX15 or 15-LO-1

• Specifically, we examined the association between a single nucleotide polymorphism at -5299G/A in the ALOX15 5'-flanking region with BMD in 319 postmenopausal Japanese women (66.7 +/- 8.9 years, mean +/- SD) [1].
• Because circumstantial evidence suggests that 12/15-LOX is a major source of oxidative stress, we investigated the protein levels and activity of this enzyme in different brain regions of histopathologically confirmed AD and control cases [2].
• The IC50 values were 0.43, 0.72, and 0.42 microg/mL, respectively, whereas the IC50 values for nordihydroguaiaretic acid (NDGA) on 5-, 12-, and 15-LOX were 2.3, 1.6, and 1.7 microg/mL, respectively [11].
• A P1 artificial chromosome clone containing the 5' region of MYBBP1A was isolated and indicates a physical linkage between MYBBP1A and the 15-lipoxygenase gene (ALOX15) [12].
• We detected 11 variations, including five polymorphisms located in the ALOX15 promoter region [13].
• Our results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression  .

Anatomical context of ALOX15

• For the remaining enzymes, the expression of COX-2, 12-LOX, and 15-LOX varied among cell lines, 60, 35, and 90%, respectively [14].
• Soybean 15-LOX, rabbit reticulocyte 15-LOX, human 15-LOX-1, and human 15-LOX-2 oxygenate 2-AG, providing 15(S)-hydroperoxyeicosatetraenoic acid glyceryl ester [15].
• Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases [16].
• Occurrence of the erythroid cell specific arachidonate 15-lipoxygenase in human reticulocytes [17].
• These results were corroborated in primary human macrophages, in which macrophages from heterozygous c.-292CT carriers expressed three times more ALOX15 mRNA than macrophages from homozygous c.-292CC carriers [13].

Associations of ALOX15 with chemical compounds

• Using specific inhibitors of LOX, blocking 12-LOX but not 5- or 15-LOX inhibited both fenretinide-induced ROS and apoptosis [18].
• 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also generated in the course of glomerular injury [19].
• A number of compounds possessing a C-2 substituted-phenyl moiety (4-Br, 4-F, and 4-OH), or a 4- or 3-(2,4-difluorophenyl)phenyl moiety, showed potent 15-LOX inhibitory activity (IC(50) values in the 0.31-0.49muM range) relative to the reference drug luteolin (IC(50)=3.2muM) [20].
• To validate this luminometric method the kinetic parameters of 15-LOX catalyzed oxygenation of linoleic acid (Km=3.7 microM, kcat=17 s-1) were determined and we observed a good agreement with previously published data obtained with a spectrophotometric assay [4].
• Moreover, we found that the kinetic constants of 15-LOX catalyzed LDL oxidation (Km=0.64 microM, kcat=0.15 s-1) are quite different from those of free fatty acid oxygenation and that the cholesterol esters are preferentially oxidized during 15-LOX/LDL interaction [4].

Physical interactions of ALOX15

• We conclude that the c.-292 T allele in the ALOX15 promoter generates a novel binding site for the transcription factor SPI1 that results in higher transcription of the gene in macrophages [13].
• Kelavkar and Badr (1999)  stated that the ALOX15 gene maps to 17p13.3 in close proximity to the tumor-suppressor gene TP53  .

Regulatory relationships of ALOX15

• Collectively, these findings suggest a new mechanism to explain the biological activity of 15-LOX-1, where 15-LOX plays a stoichiometric role in activating a DNA-dependent protein kinase-dependent pathway that leads to p53-dependent growth arrest [21].
• Since 15-LOX metabolites have potent anti-inflammatory actions, our data suggest that IL-4 might downregulate rheumatoid inflammation via the induction of 15-LOX and its metabolites [22].
• RESULTS: RT-PCR results showed that human RA type B synoviocytes expressed a reticulocyte-type 15-LOX [23].

Other interactions of ALOX15

• It was found that OAS-1000 inhibits PGHS-1 activity with an IC-50 value of 80.3 microM, but had much less activity versus PGHS-2 enzyme and no activity versus the 15-LOX enzyme [24].
• The present study was undertaken to investigate whether increased levels of leukotrienes are balanced by the antiinflammatory/antifibrotic cyclooxygenase (COX)- and 15-LOX-derived eicosanoids in the lungs of patients with SLD [25].
• Targeting the 5-LOX/15-LOX balance may be of practical value in the treatment of SLD [25].
• OBJECTIVE: To clarify the role of interleukin-4 (IL-4) in the expression of 15-lipoxygenase (15-LOX), whose metabolities are known to suppress the inflammatory reaction, in freshly prepared rheumatoid synovial cells [22].
• Arachidonate 15-lipoxygenase of reticulocyte-type in human rheumatoid arthritis type B synoviocytes and modulation of its activity by proinflammatory cytokines [23].

Analytical, diagnostic and therapeutic context of ALOX15

• Using quantitative Western blot analysis we demonstrated that in affected frontal and temporal regions of AD brains the amount of 12/15-LOX was higher compared with controls, whereas no difference between the two groups was detected in the cerebellum [2].
• From tissues expressing the long 15-LOX mRNA2, two to three unidentified polypeptides with molecular weights of 53-55 and 90-93 kDa which bound to DICE2 were isolated by RNA affinity chromatography [26].
• In anaemic animals, northern blotting showed that 15-LOX mRNA2 was predominantly expressed in non-erythroid tissues, whereas 15-LOX mRNA1 was exclusively expressed in red blood cells and bone marrow [26].
• HCE cells were transfected with plasmids to express green fluorescent (GFP) fusion proteins of 15-LOX-1 and -2, and in vivo laser confocal microscopy was performed to determine the subcellular localization of the 15-LOX fusion proteins [27].
• Between passages 4 and 8, reticulocyte-type 15-LOX expression in these cells was determined by reverse transcription-polymerase chain reaction (RT-PCR) in situ and confirmed by classical RT-PCR analysis followed by enzymatic digestion [23].

References