lipoxygenase pathway
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Lipoxygenázy (LOX, linoleate: oxygen oxidoreductases, EC 1.13.11.12) tvoria rodinu dioxygenáz, ktoré obsahujú nehémové, nesulfidové železo. Vyskytujú sa nielen u živočíchov, ale aj u rastlín. Ich prítomnosť bola dokázaná aj v koraloch, machu, hubách a v niektorých baktériách. LOX katalyzujú polohovo- a stereo- špecifickú inzerciu molekulového kyslíka do molekuly nenasýtenej mastnej kyseliny s cis,cis-1,4-pentadiénovým systémom za vzniku príslušných hydroperoxidových derivátov. Tento krok dioxygenácie vyúsťuje do kaskády reakcií, ktoré sa označujú ako lipoxygenázová (oktadekánová) cesta. Koncové produkty tejto cesty (nazývané oxylipíny) zohrávajú u rastlín významnú úlohu ako signálne molekuly pri hojení rán a pri obranných procesoch. V živočíšnych organizmoch sú zase zapojené do procesov zápalových reakcií, astmy a ochorení srdca.
Lipoxygenases (LOX, linoleate: oxygen oxidoreductases, EC 1.13.11.12) constitute a family of dioxygenases, which contain non-heme, non-sulfide iron. These enzymes occur not only in animals, but in plants as well. They have been detected in coral, moss, fungi and also in some bacteria. LOXs catalyse the regiospecific and stereospecific insertion of molecular oxygen into the molecule of polyunsaturated fatty acid with the cis,cis- -1,4-pentadiene system to yield the corresponding hydroperoxides. This step of dioxygenation leads to a cascade of reactions called the lipoxygenase (octadecanoid) pathway. The products of this pathway (called oxylipins) play an important role as signal molecules in wound healing and defence processes in plants. In animals they are involved in inflammation, asthma and heart diseases.
- MeSH
- biochemické jevy * MeSH
- buněčná diferenciace MeSH
- iniciace genetické transkripce MeSH
- lipoxygenasy * fyziologie MeSH
- membránové potenciály MeSH
- membránové transportní proteiny MeSH
- nenasycené mastné kyseliny chemie MeSH
- oxylipiny * chemie MeSH
- rostliny MeSH
- signální transdukce MeSH
- transkripční faktory MeSH
- Publikační typ
- přehledy MeSH
The treatment of human promyelocytic leukemia cell lines HL-60, and to some extent NB-4, with 1alpha,25-dihydroxyvitamin D(3) (VD3) induces differentiation toward the monocytic/macrophage lineage, demonstrated by the increased expression of CD11b and CD14, and the production of opsonized zymosan particles (OZP)-stimulated reactive oxygen species (ROS). Moreover, in more sensitive HL-60 cells, increased expression of 5-lipoxygenase (5-LPO), Mcl-1, IkappaB, and c-Jun, accompanied by the activation of p38 MAPK, was detected. These VD3 effects on HL-60 cell differentiation were significantly potentiated by 5-LPO inhibitors MK-886 and AA-861 and were inverted by SB202190 (SB), a p38 MAPK inhibitor. The inhibition of differentiation by SB was demonstrated by a reduction of CD14 expression and by a decrease in OZP-activated ROS production. These results indicated that p38 MAPK pathway is involved in 5-LPO inhibitors-dependent potentiation of VD3-induced monocytic differentiation.
- MeSH
- arachidonát-5-lipoxygenasa genetika MeSH
- benzochinony farmakologie MeSH
- buněčná diferenciace účinky léků MeSH
- HL-60 buňky MeSH
- indoly farmakologie MeSH
- inhibitory lipoxygenas farmakologie MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- monocyty cytologie MeSH
- vitamin D analogy a deriváty farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Leukotriény (LT), zahŕňajúce cysteinyl LT a LTB4, sú významné lipidové mediátory zúčastňujúce sa signalizácie v mnohých zápalových procesoch. Proces premeny kyseliny arachidónovej na leukotriény môžeme označovať ako leukotriénovú cestu. Kľúčovým enzýmom je 5-lipoxygenáza – dioxygenáza s nehémovo viazaným centrálnym iónom železa, ktorý v katalytickom komplexe s membránovým 5-lipoxygenázu aktivujúcim proteínom tvorí 5-hydroperoxyeikozatetraénovú kyselinu. V ďalších krokoch sa zapájajú leukotrién A4-hydroláza alebo leukotrién C4-syntáza. Vďaka pokroku z posledných rokov v oblasti röntgenovej štruktúrnej analýzy a odhalenia 3D štruktúry biokatalyzátorov, najmä ich aktívnych centier, sa vývoj nových liečiv výrazne urýchlil. Tento zložitý enzymaticky kontrolovaný proces ponúka viacero možností modulácie a predstavuje tak nové prístupy nielen k liečbe typických zápalových ochorení, ale aj v terapii aterosklerózy a nádorových ochorení.
Leukotrienes (LT), namely cysteinyl LT and LTB4, are potent lipid mediators taking part in the signal pathways of many inflammatory processes. The arachidonic acid transformation into leukotrienes can be signed as the leukotriene pathway. The key enzyme is 5-lipoxygenase, a dioxygenase containing a nonheme-bound ferric central ion, which in the catalytic complex with 5-lipoxygenase activating protein forms 5-hydroperoxyeicosatetraenoic acid. In the next steps this process involves leukotriene A4- -hydrolase or leukotriene C4-synthase. According to the progress in recent years in the area of X-ray structural analysis and revealed 3D structure of these biocatalysts, especially their active sites, the development of new drugs markedly accelerated. This complicated enzymatically controlled process offers several possibilities of modulation and presents new approaches to the treatment of typical inflammatory diseases as well as in the therapy of atherosclerosis and cancer.
- MeSH
- anafylaxe MeSH
- arachidonát-5-lipoxygenasa MeSH
- ateroskleróza diagnóza MeSH
- časná detekce nádoru MeSH
- časná diagnóza MeSH
- leukotrieny MeSH
- lidé MeSH
- receptory spřažené s G-proteiny MeSH
- zánět diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Leukotrienes (LTs) and sphingolipids are critical lipid mediators participating in numerous cellular signal transduction events and developing various disorders, such as bronchial hyperactivity leading to asthma. Enzymatic reactions initiating production of these lipid mediators involve 5-lipoxygenase (5-LO)-mediated conversion of arachidonic acid to LTs and serine palmitoyltransferase (SPT)-mediated de novo synthesis of sphingolipids. Previous studies have shown that endoplasmic reticulum membrane protein ORM1-like protein 3 (ORMDL3) inhibits the activity of SPT and subsequent sphingolipid synthesis. However, the role of ORMDL3 in the synthesis of LTs is not known. In this study, we used peritoneal-derived mast cells isolated from ORMDL3 KO or control mice and examined their calcium mobilization, degranulation, NF-κB inhibitor-α phosphorylation, and TNF-α production. We found that peritoneal-derived mast cells with ORMDL3 KO exhibited increased responsiveness to antigen. Detailed lipid analysis showed that compared with WT cells, ORMDL3-deficient cells exhibited not only enhanced production of sphingolipids but also of LT signaling mediators LTB4, 6t-LTB4, LTC4, LTB5, and 6t-LTB5. The crosstalk between ORMDL3 and 5-LO metabolic pathways was supported by the finding that endogenous ORMDL3 and 5-LO are localized in similar endoplasmic reticulum domains in human mast cells and that ORMDL3 physically interacts with 5-LO. Further experiments showed that 5-LO also interacts with the long-chain 1 and long-chain 2 subunits of SPT. In agreement with these findings, 5-LO knockdown increased ceramide levels, and silencing of SPTLC1 decreased arachidonic acid metabolism to LTs to levels observed upon 5-LO knockdown. These results demonstrate functional crosstalk between the LT and sphingolipid metabolic pathways, leading to the production of lipid signaling mediators.
- MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- ikosanoidy analýza metabolismus MeSH
- membránové proteiny metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- serin-C-palmitoyltransferasa metabolismus MeSH
- sfingolipidy analýza metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63-94%, cyclooxygenase-2 (COX-2) activity in the range of 20-44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72-84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41-68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway.
- MeSH
- aktivace enzymů účinky léků MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- cyklooxygenasa 1 metabolismus MeSH
- cyklooxygenasa 2 metabolismus MeSH
- flavonoidy farmakologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- katalýza MeSH
- lidé MeSH
- quercetin farmakologie MeSH
- stilbeny farmakologie MeSH
- víno * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Lipoxygenases (LOX; linoleate:oxygen oxidoreductase, EC 1.13.11.12) are a family of dioxygenases that do not contain hem-bonded iron at the active site. They catalyze peroxidation of polyunsaturated fatty acids, in particular linolic and linolenic acids, which gives hydroperoxy derivatives of (9S)- or (13S)-polyunsaturated fatty acids (9-LOX or 13-LOX, respectively). Lipid peroxidation is important in plant evolution and for their response to various forms of stress, both of biotic and abiotic origin. LOX is the starting enzyme of the lipoxygenase metabolic pathway producing oxylipins such as signal molecules, antimicrobial and antifungal compounds.
Wounding, one of the most intensive stresses influencing plants ontogeny and lifespan, can be induced by herbivory as well as by physical factors. Reactive oxygen species play indispensable role both in the local and systemic defense reactions which enable "reprogramming" of metabolic pathways to set new boundaries and physiological equilibrium suitable for survival. In our current study, we provide experimental evidence on the formation of singlet oxygen (1O2) after wounding of Arabidopsis leaves. It is shown that 1O2 is formed by triplet-triplet energy transfer from triplet carbonyls to molecular oxygen. Using lipoxygenase inhibitor catechol, it is demonstrated that lipid peroxidation is initiated by lipoxygenase. Suppression of 1O2 formation in lox2 mutant which lacks chloroplast lipoxygenase indicates that lipoxygenase localized in chloroplast is predominantly responsible for 1O2 formation. Interestingly, 1O2 formation is solely restricted to chloroplasts localized at the wounding site. Data presented in this study might provide novel insight into wound-induced signaling in the local defense reaction.
- MeSH
- Arabidopsis MeSH
- fenotyp MeSH
- fluorescenční protilátková technika MeSH
- konfokální mikroskopie MeSH
- lipoxygenasa metabolismus MeSH
- lipoxygenasy genetika MeSH
- mastné kyseliny metabolismus MeSH
- molekulární zobrazování MeSH
- mutace MeSH
- proteiny huseníčku genetika MeSH
- rány a poranění metabolismus MeSH
- singletový kyslík metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated the role of the 5-lipoxygenase (5-LOX) pathway of arachidonic acid metabolism in tumour necrosis factor-alpha (TNF-alpha)-induced differentiation of human leukemic HL-60 cells using MK-886, an inhibitor of 5-LOX activating protein. MK-886 augmented cell cycle arrest and differentiation induced by TNF-alpha; however, both effects were probably 5-LOX-independent, because a general LOX inhibitor, NDGA, had no effect. Apoptosis was significantly elevated after combined TNF-alpha and MK-886 treatment, which could be partially associated with changes of Mcl-1 protein expression. NF-kappaB signalling or activation of JNKs were not modulated by MK-886. Thus, in addition to apoptosis, MK-886 can enhance TNF-alpha-induced differentiation.
- MeSH
- apoptóza MeSH
- arachidonát-5-lipoxygenasa metabolismus MeSH
- buněčná diferenciace MeSH
- buněčný cyklus MeSH
- časové faktory MeSH
- financování organizované MeSH
- HL-60 buňky MeSH
- indoly farmakologie MeSH
- inhibitory lipoxygenas farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- signální transdukce MeSH
- TNF-alfa metabolismus MeSH
- viabilita buněk MeSH
- Check Tag
- lidé MeSH
Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.
- MeSH
- buněčné linie MeSH
- cyklooxygenasy metabolismus MeSH
- inhibitory enzymů farmakologie MeSH
- lidé MeSH
- lipoxygenasy metabolismus MeSH
- NF-kappa B antagonisté a inhibitory MeSH
- prenylace * MeSH
- signální transdukce účinky léků MeSH
- stilbeny farmakologie MeSH
- transkripční faktor AP-1 antagonisté a inhibitory MeSH
- zánět prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
