Protein Kinase A Inhibits Leukotriene Synthesis by Phosphorylation of 5-Lipoxygenase on Serine 523

Luo, Ming; Jones, Scott; Phare, Susan M.; Coffey, Michael; Peters‐Golden, Marc; Brock, Thomas G.

doi:10.1074/jbc.m312568200

Cited by 112 publications

(88 citation statements)

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“…Increases in intracellular levels of cAMP can inhibit LT synthesis by a variety of enzymatic mechanisms (90), and commonly used cAMP-elevating drugs such as ␤-adrenergic agonists, theophylline, and phosphodiesterase inhibitors have been reported to inhibit LT synthesis by leukocytes (91). Although its clinical significance is unclear, in vivo cAMP elevation has been reported to impair pulmonary bacterial clearance in an animal model of pneumonia (92).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

The Journal of Immunology

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278

244

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Leukotrienes are bronchoconstrictor and vasoactive lipid mediators that are targets in the treatment of asthma. Although they are increasingly recognized to exert broad proinflammatory effects, their role in innate immune responses is less well appreciated. These molecules are indeed synthesized by resident and recruited leukocytes during infection. Acting via cell surface G protein-coupled receptors and subsequent intracellular signaling events, they enhance leukocyte accumulation, phagocyte capacity for microbial ingestion and killing, and generation of other proinflammatory mediators. Interestingly, a variety of acquired states of immunodeficiency, such as HIV infection and malnutrition, are characterized by a relative deficiency of leukotriene synthesis. The data reviewed herein point to leukotrienes as underappreciated yet highly relevant mediators of innate immunity.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Peters‐Golden¹,

Canetti²,

Mancuso

et al. 2005

The Journal of Immunology

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278

244

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“…The mechanisms involved here are still not fully understood, but there is evidence for cells with nuclear 5-LO to produce more LTB 4 than the same cells with cytoplasmic 5-LO (26). Phosphorylation by protein kinase (mitogen-activated protein) A on Ser523 can decrease 5-LO activity, whereas phosphorylation on Ser271 by MAP kinase (mitogen-activated protein) activated protein 2 and on Ser663 by extracellular signalregulated kinase can increase it (27)(28)(29).…”

Section: Regulation Of Lt Synthesismentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC 4 , LTD 4 and, LTE 4 ) and the dihydroxy leukotriene LTB 4 are generated by a series of enzymes/ proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotr...

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“…Recently, 5-LO kinases, namely the p38 MAPK-regulated MAP-KAPK-2/3, the ERK1/2, CaMKII and PKA [54], [55], [56], [57] the respective upstream signaling pathways could block cellular 5-LO product formation by such routes as well. In fact, the flavonoid quercetin 11 that suppresses 5-LO product synthesis also blocks the ERK1/2 and p38 MAPK pathway [58], [59], and plantderived tyrosine kinase inhibitors such as genistein reduced 5-LO activation in HL60 cells [47].…”

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

153

135

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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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Protein Kinase A Inhibits Leukotriene Synthesis by Phosphorylation of 5-Lipoxygenase on Serine 523

Cited by 112 publications

References 50 publications

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Leukotrienes: Underappreciated Mediators of Innate Immune Responses

Leukotriene pathway genetics and pharmacogenetics in allergy

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

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