5-Lipoxygenase: regulation of expression and enzyme activity

Rådmark, Olof; Werz, Oliver; Steinhilber, Dieter; Samuelsson, Bengt

doi:10.1016/j.tibs.2007.06.002

Cited by 414 publications

(398 citation statements)

References 94 publications

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“…Among the LOX family, the 5-LOX isoform has been shown to be involved in tumorigenesis, as its inhibition blocks proliferation of a wide variety of tumoral cells, including lymphoid and myeloid cancer cells (Pidgeon et al, 2007). We found that NPM-ALK( þ ) ALCLs overexpressed 5-LOX (Figure 4a), as already shown for other cancers (Pidgeon et al, 2007;Radmark et al, 2007). The NPM-ALK-dependent increase in 5-LOX required ALK activity in lymphoid cells (Supplementary Figure 1a).…”

supporting

confidence: 80%

“…Figure 4a and Supplementary Figure 1b Figure 1b), suggesting that 5-LOX was the predominant isoform in the NPM-ALK( þ ) cells tested, and therefore the most likely target of NDGA treatment. Phosphorylation of Ser 523 of 5-LOX by protein kinase A (PKA) suppresses its activity, whereas dephosphorylation leads to activation and nuclear translocation of the enzyme (Radmark et al, 2007). Accordingly, we observed a robust phosphorylation of Ser 523 in NPM-ALK(À) cells, that disappeared on expression of the oncogene (Figure 4a).…”

mentioning

confidence: 84%

“…Interestingly, the MAPK p38 was activated by NDGA. There are conflicting reports in the literature as to whether 5-LOX, one of the LOX family members often found associated with cancers, regulates or is regulated by p38 (Radmark et al, 2007). Differences seem to be due to cell types, with p38 and ERK being activators of 5-LOX mostly in neutrophils (Flamand et al, 2002).…”

mentioning

confidence: 99%

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Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

et al. 2009

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confidence: 80%

mentioning

confidence: 84%

mentioning

confidence: 99%

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Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

et al. 2009

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“…Ca 2+ binds to the regulatory C2-like domain, mediates binding of 5-LO to PC-containing membranes or lipid vesicles, lowers the K m value for AA as substrate, and decreases the requirement of 5-LO for activating LOOH, which altogether potently enhances 5-LO catalysis in vitro [21], [24], [31]. In the cell, Ca 2+ facilitates 5-LO association with the nuclear membrane and protects 5-LO activity against GPx activity [48].…”

Section: Activation Pathways Of 5-lo In the Cellmentioning

confidence: 99%

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Werz¹

2007

Planta Med

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The biosynthesis of leukotrienes (LTs) is initiated by the transformation of free arachidonic acid to LTA 4 by 5-lipoxygenase (5-LO). Subsequent enzymatic conversion of LTA 4 yields LTB 4 and the cysteinyl-LTs C 4 , D 4 and E 4 . LTs have prominent functions in pathophysiology and are connected to numerous disorders including bronchial asthma, allergic rhinitis, inflammatory bowel and skin diseases, rheumatoid arthritis, cancer, osteoporosis and cardiovascular diseases. Pharmacological and genetic interruption of the 5-LO pathway or blockade of LT receptors, serving as means for intervention with LTs, may be of therapeutic value for certain related disorders. Natural or plant-derived substances were among the first 5-LO inhibitors identified in the early 1980 s. To date, a huge number of diverse plant-derived compounds have been reported to interfere with 5-LO product synthesis. However, many investigations have addressed the efficacy of a given compound solely in cellular test systems and analysis of direct interference with 5-LO has been neglected. In the first part of this review, the biology and molecular pharmacology of the 5-LO pathway is summarized in order to understand its overall regulation and complexity as well as to comprehend the possible points of attack of compounds that eventually lead to inhibition of 5-LO product formation in intact cells. In the second part, natural compounds that interfere with 5-LO product formation are compiled and grouped into structural classes, and the underlying molecular mechanisms and structureactivity relationships are discussed.

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“…The addition of calcium stimulates both the oxygenation and dehydration reactions of 5-LOX. This enzyme is expressed mainly in leukocytes, in line with the function of leukotrienes as mediators of immune reactions [3]. Granulocytes, monocytes/macrophages, mast cells, dendritic cells and B lymphocytes express 5-LOX, whereas platelets, endothelial cells, T cells and erythrocytes do not.…”

Section: Introductionmentioning

confidence: 87%

Discovery of Novel 5-lox Inhibitors: Pharmacophore Design, Homology and Docking Studies

Kalva¹,

Vadivelan²,

Jagarlapudi³

2011

IJBBB

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Abstract-Inhibition of leukotriene biosynthesis has been extensively studied as a potential for the development of novel therapies for inflammation, respiratory diseases and, in particular, for asthma. We have designed specific functional inhibitors against 5-Lipoxygenase (5-LOX) using several virtual screening techniques like Homology modeling, MD simulations, Docking and Pharmacophore studies. We have identified 6 analogues of novel 5-LOX inhibitors (IC50 < 19 nM) using pharmacophore models and docking studies and their drug like properties were evaluated. These 6 compounds can be taken for further study including synthesis.

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5-Lipoxygenase: regulation of expression and enzyme activity

Cited by 414 publications

References 94 publications

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas

Inhibition of 5-Lipoxygenase Product Synthesis by Natural Compounds of Plant Origin

Discovery of Novel 5-lox Inhibitors: Pharmacophore Design, Homology and Docking Studies

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