# ALOX5

## Overview
The ALOX5 gene encodes the enzyme arachidonate 5-lipoxygenase, a crucial catalyst in the biosynthesis of leukotrienes, which are lipid mediators involved in inflammatory and immune responses. This enzyme, classified as a lipoxygenase, facilitates the oxygenation of arachidonic acid to produce leukotriene A4, a precursor to various other biologically active leukotrienes. The activity and function of the ALOX5 enzyme are essential in physiological processes such as host defense and pathophysiological conditions including asthma, atherosclerosis, and other inflammatory diseases. The regulation of this enzyme involves complex interactions with cellular proteins and is influenced by genetic factors that affect its expression and activity, making it a significant target for therapeutic interventions in diseases mediated by leukotriene pathways (Haeggström2011Lipoxygenase; Rådmark20155-Lipoxygenase).

## Structure
The molecular structure of the ALOX5 protein, a key enzyme in leukotriene biosynthesis, is characterized by a two-domain architecture. The N-terminal domain, approximately 15 kDa in size, consists of several parallel and anti-parallel β-sheets. This domain is crucial for activity regulation and membrane binding. The C-terminal domain is composed of several helices and is responsible for housing the catalytic nonheme iron within the substrate-binding pocket. The overall structure of ALOX5 suggests a significant degree of structural flexibility and potential for interdomain movement, which are critical for its enzymatic function (Kuhn2015Mammalian).

Crystal structures of ALOX5 variants, including a stabilized version of the human protein and a phosphorylation-mimicking mutant (Ser663Asp), provide insights into the enzyme's reaction specificity. These structures reveal alterations in the enzyme's specificity from 5- to 15-lipoxygenation, although interpretations from these mutants require caution as they have not been confirmed in native ALOX5 orthologs across different species (Kuhn2015Mammalian).

Additionally, ALOX5 may exhibit the ability to form dimers in aqueous solutions, a behavior that is supported by recent molecular studies and could contribute to its allosteric properties (Kuhn2015Mammalian).

## Function
The ALOX5 gene encodes the enzyme 5-lipoxygenase (5-LOX), which is pivotal in the biosynthesis of leukotrienes from arachidonic acid. These leukotrienes are critical lipid mediators involved in various inflammatory and immune responses. The enzyme catalyzes the insertion of oxygen into arachidonic acid, forming an unstable epoxide leukotriene A4 (LTA4), which can be further metabolized into other leukotrienes such as leukotriene B4 (LTB4) and cysteinyl leukotrienes (CysLTs). LTB4 acts as a potent leukocyte chemoattractant, while CysLTs are involved in increasing vascular permeability and bronchoconstriction (Poirier2020LPS; Rådmark20155-Lipoxygenase).

5-LOX activity is tightly regulated within cells and requires translocation to the perinuclear region to interact with FLAP (5-Lipoxygenase-activating protein) for efficient leukotriene production. This translocation is triggered by external stimuli that activate signaling pathways influencing the enzyme's activity and localization (Rådmark20155-Lipoxygenase). Additionally, the enzyme's function is modulated by phosphorylation events and its interaction with cellular membranes, which are crucial for its catalytic activity (Haeggström2011Lipoxygenase).

In healthy cells, the production of leukotrienes by ALOX5 plays a significant role in normal host defense mechanisms, mediating responses to infections and injuries by regulating inflammation and immune cell recruitment (Rådmark20075-Lipoxygenase:).

## Clinical Significance
Mutations and polymorphisms in the ALOX5 gene, which encodes arachidonate 5-lipoxygenase, have significant clinical implications in various inflammatory and atopic disorders. Variants in the ALOX5 promoter, particularly affecting the number of Sp1/Egr-1 binding motifs, influence leukotriene production and are linked to variations in asthma severity. Individuals with certain deletional variants exhibit more severe asthma symptoms and a diminished response to leukotriene pathway inhibitors (Kalayci2005ALOX5). Similarly, these genetic variants are associated with increased leukotriene production, impaired lung function, and poorer asthma control, particularly noted in individuals carrying two copies of the minor variant (Mougey2013ALOX5).

In cardiovascular disease, ALOX5 gene alterations are linked to increased intima-media thickness in atherosclerosis, suggesting a role in the disease's progression (Mougey2013ALOX5). Additionally, ALOX5 polymorphisms have been implicated in Alzheimer's disease, where its expression is associated with increased amyloid-beta production and tau protein phosphorylation, key components in the disease's pathology (Šerý2016Arachidonate).

Furthermore, sex-related differences in ALOX5 gene polymorphisms might influence the severity and treatment response of lung inflammatory diseases differently in men and women, indicating a potential variable impact based on gender (Mirra2023Association). These findings underscore the importance of ALOX5 in the pathophysiology of multiple diseases, highlighting its potential as a target for therapeutic intervention.

## Interactions
ALOX5, or arachidonate 5-lipoxygenase, interacts with various proteins that influence its function and regulation. One significant interaction is with MAD1L1, a protein involved in the mitotic spindle assembly checkpoint. The p.Met146Lys mutation in ALOX5 disrupts its interaction with MAD1L1, leading to a loss of physical protein-protein interaction (PPI) which is crucial as both proteins play roles in cancer development and progression (Cheng2021Comprehensive). This mutation has been experimentally validated to result in the loss of interaction using a yeast two-hybrid (Y2H) assay (Cheng2021Comprehensive).

Additionally, ALOX5 is regulated at the gene level through interactions with various proteins that bind to its promoter. Notable among these are Sp-family proteins (Sp1, Sp2, Sp3), KLF family members (KLF13, KLF16), and other zinc finger proteins such as MAZ, PRDM10, VEZF1, ZBTB7A, ZNF281, and ZNF579. These interactions are crucial for understanding the complex regulation of the ALOX5 gene, potentially impacting therapeutic approaches for diseases like asthma and certain cancers where leukotriene pathways are involved (Schlag2020Analysis).


## References


[1. (Kuhn2015Mammalian) Hartmut Kuhn, Swathi Banthiya, and Klaus van Leyen. Mammalian lipoxygenases and their biological relevance. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1851(4):308–330, April 2015. URL: http://dx.doi.org/10.1016/j.bbalip.2014.10.002, doi:10.1016/j.bbalip.2014.10.002. (428 citations) 10.1016/j.bbalip.2014.10.002](https://doi.org/10.1016/j.bbalip.2014.10.002)

[2. (Mougey2013ALOX5) E. Mougey, J. E. Lang, H. Allayee, W. G. Teague, A. J. Dozor, R. A. Wise, and J. J. Lima. <scp>alox</scp>5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma. Clinical &amp; Experimental Allergy, 43(5):512–520, April 2013. URL: http://dx.doi.org/10.1111/cea.12076, doi:10.1111/cea.12076. (59 citations) 10.1111/cea.12076](https://doi.org/10.1111/cea.12076)

[3. (Rådmark20075-Lipoxygenase:) Olof Rådmark, Oliver Werz, Dieter Steinhilber, and Bengt Samuelsson. 5-lipoxygenase: regulation of expression and enzyme activity. Trends in Biochemical Sciences, 32(7):332–341, July 2007. URL: http://dx.doi.org/10.1016/j.tibs.2007.06.002, doi:10.1016/j.tibs.2007.06.002. (364 citations) 10.1016/j.tibs.2007.06.002](https://doi.org/10.1016/j.tibs.2007.06.002)

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