title: The role of lipoxygenases in pathophysiology; new insights and future perspectives.
abstract: Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. LOX enzymes are expressed in immune, epithelial, and tumor cells that display a variety of physiological functions, including inflammation, skin disorder, and tumorigenesis. In the humans and mice, six LOX isoforms have been known. 15-LOX, a prototypical enzyme originally found in reticulocytes shares the similarity of amino acid sequence as well as the biochemical property to plant LOX enzymes. 15-LOX-2, which is expressed in epithelial cells and leukocytes, has different substrate specificity in the humans and mice, therefore, the role of them in mammals has not been established. 12-LOX is an isoform expressed in epithelial cells and myeloid cells including platelets. Many mutations in this isoform are found in epithelial cancers, suggesting a potential link between 12-LOX and tumorigenesis. 12R-LOX can be found in the epithelial cells of the skin. Defects in this gene result in ichthyosis, a cutaneous disorder characterized by pathophysiologically dried skin due to abnormal loss of water from its epithelial cell layer. Similarly, eLOX-3, which is also expressed in the skin epithelial cells acting downstream 12R-LOX, is another causative factor for ichthyosis. 5-LOX is a distinct isoform playing an important role in asthma and inflammation. This isoform causes the constriction of bronchioles in response to cysteinyl leukotrienes such as LTC4, thus leading to asthma. It also induces neutrophilic inflammation by its recruitment in response to LTB4. Importantly, 5-LOX activity is strictly regulated by 5-LOX activating protein (FLAP) though the distribution of 5-LOX in the nucleus. Currently, pharmacological drugs targeting FLAP are actively developing. This review summarized these functions of LOX enzymes under pathophysiological conditions in mammals.
authors: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Ohkura, Setagaya-ku, Tokyo 157-8535, Japan. Electronic address: mashima-r@ncchd.go.jp.
authors: Ryuichi
authors: R
authors: Mashima
authors: Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Ohkura, Setagaya-ku, Tokyo 157-8535, Japan.
authors: Torayuki
authors: T
authors: Okuyama
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002986:Clinical Trials as Topic; D015870:Gene Expression; D006801:Humans; D007057:Ichthyosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007211:Indoles / Q000627:therapeutic use*; D008084:Lipoxygenase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010421:Pentanoic Acids / Q000627:therapeutic use*
chemical_list: C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D018927:Anti-Asthmatic Agents; D007211:Indoles; D010421:Pentanoic Acids; C511051:ALOXE3 protein, human; D008084:Lipoxygenase; C514086:ALOX12B protein, human; D001092:Arachidonate 12-Lipoxygenase; C476558:ALOX12 protein, human; C515716:ALOX15 protein, human; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase
keywords: Lipoxygenase; Phenotype; Resolvins; Signal transduction