https://www.caymanchem.com/news/sphingosine-1-phosphate-vs-ceramide
( Tämä aihe on jatkoa K-vitamiiniaineenvaihduntaa käsiteleviin muistiinpanoihini, koska Kvitamiini on sfingomyeliinin aineenvaihdunnan alku ja pääte kohdissa vaikuttava koentsyymi. Merkitsin linkin STUK kirjaani numero 3 Säteilyn käyttö, sivulle 182 ja piirsin artikkelin kaavakuvat myös muistiin. Asetan linkin Blogiin , jossa kirjoitan eri molekyleistä rasva-aineenvaihdunnan alueelta.)
Sittaatti netistä: Aihe on käsitelty auringon UV- säteilyn polttovaikutuksista katsoen. Se vaikuttaa jonisoivasti ja tekee vapaita radikaaleja. ne taas vapauttavat ihon pintakerroksen sfingomyeliinistä solunsisisiä keramideja ja ne aihuttavat reaktiosarjan, joka johtaa lopulta slun kuolemaan. Tässä keramidien katabolisessa tiessä on kuitenkin yksi vaihe, sfingosiini-1-fosfaatin muodostuminen (S1P). Se on molekyyli, josta artikkeli kertoo. Katsotaan mitä sanottavaa hra Brockin konseptissa on mainittuna.
Aluksi toistetaan synoptinen kaava sfinganiinin muodostuksesta alkutekijöistä soluaineenvaihdunnassa: aktivoidusta palmitiinihaposta joka kondensoituu aktivoidun seriiniaminohapon kanssa reaktiossa, jossa tarvitaan apuna mm ravintoperäoisiä vitamiineja entsyymien apuna: K1-vitamiinivaikutusta ja B6 vitamiinia sekä koentsyymi A:ta. Sfingomyeliinin muodostus on hyvin tärkeä ihmisen solukalvoille, varsinkin aivostossa ja hermostossa, myeliinitupessa ja myös ihon suojakerroksissa. Toisaalta sfingomyeliinimetaboliiteista (SMM) tunnetaan myös onkologian alueen aineksia, jotka signaloivat. Sfingomyeliinin hydrolyysissä muodostuu myös sfingosiini (So) ja siitä on suotuisissa oloissa mahdollinen salvage-tie takaisin kohti keramidimuotoa ja uudelleen sfingolipideihin... tai Sfingosiini fosforyloituu: muodostuu S-1-P.
Sfingomyeliinin muodostuksen kartta on "erikoisen tiivisti säädelty suljettu ympyrä" sikäli että siihen johtaa yksi tie ja siitä pääsee ulos vain yhtä tietä normaalisti - poikkeukset ovat harhateitä tavalla tai toisella. Evolutionaalisti ajatellen tämän normaalitien täytyy olla voitokas, koska ihmiskunta vain lisääntyy ja kasvaa täällä auringon alla ja pysyy vedenpitävänä - aikansa, jopa yli sata vuotta joskus. Eri asia, jos ihmiset koettavat pois maaallon suojakerroksista jonisoivaan avaruuteen. luulisi että se vähentää ihmiskunnan keskimääräistä ikää.
Sphingosine-1-Phosphate vs. Ceramide: The Battle of the Burn
Sphingosine-1-Phosphate vs. Ceramide: The Battle of the Burn
Article from 2012-02-01
By Thomas G. Brock, Ph.D.
The luxurious warmth of the sun's rays on the face and shoulders slowly, subtly, gives way to redness and tenderness. Without attention, continued exposure produces a painful burn, followed days later by sloughing of a layer of dead skin tissue. This familiar experience is one demonstration of the ability of ionizing radiation, in the form of ultraviolet light from the sun, to generate reactive oxygen species (ROS) that trigger the release of ceramide within cells, leading to cell death. Remarkably, the effects of ceramide can be diminished by its related metabolite, sphingosine 1-phosphate (S1P). This article introduces these lipids and their complex interrelationship.
Ceramide Metabolism
Sphingolipids are, like phospholipids, integral components of biological membranes. Ceramide, the simplest of the sphingolipids, is composed of a sphingosine base and an amide-linked acyl chain of variable length. Ceramide can be synthesized de novo in the endoplasmic reticulum through the serine palmitoyl transferase pathway, which involves the production of the intermediate sphinganine and its conversion to the immediate precursor dihydroceramide by ceramide synthases, CerS (Figure 1). Interestingly, CerS was initially identified in yeast as the longevity assurance gene 1 (LAG1), because deletion of LAG1 prolongs the replicative lifespan of Saccharomyces cerevisiae. The mouse homolog of LAG1 is called longevity assurance homolog 1 (LASS1) or upstream of growth and differentiation factor 1 (UOG1). LASS1 activity, which specifically regulates the synthesis of C18-ceramide, determines cell longevity rather than mouse aging, since reduced activity is associated with a proliferative, cancerous phenotype.1
(Katso linkistä KAAVA) ( Alla kuvataan järjestelmän entsyymeitä)
Figure 1. Ceramide synthesis and metabolism
Ceramide can be rapidly released from membrane-associated sphingomyelin by sphingomyelinases (SMase, or sphingomyelin phosphodiesterases). There are several SMases in man, including three neutral SMases that have greatest activity at neutral pH and an acidic SMase (ASMase) that, while active at neutral pH, shows increased functionality in acidic environments. This latter enzyme is abundant in lysosomal membranes but can also be found in plasma membranes associated with lipid rafts. Defects in ASMase cause Niemann-Pick disease, a lysosome storage disease. Lymphoblasts from Niemann-Pick patients fail to respond to ionizing radiation with ceramide generation and apoptosis.2 These abnormalities are reversed by the transfected expression of ASMase, demonstrating the central role of this SMase in radiation-induced apoptosis. Furthermore, ASMase is activated by ROS as well as by peroxynitrite, a product formed from nitric oxide and superoxide.3 Thus, ROS produced by ionizing radiation activates ASMase, causing the production of ceramide.
Ceramide can be de-acylated by ceramidases to give sphingosine (So) plus a carboxylate, and sphingosine in turn can be phosphorylated by sphingosine kinases (SPHK) to produce S1P. S1P is a potent signal transduction-inducing molecule that is involved in such diverse biological processes as cell proliferation, differentiation, migration, and cell survival. There are at least two human ceramidases, an acidic form that is associated with lysosomes and a neutral ceramidase that is associated with the plasma membrane. Similarly, there are two human SPHK forms. SPHK1, the better studied form, is activated by many stimuli, including TGF-β, IL-1β, TNF-α, platelet-derived growth factor, insulin, and LPS. Phosphorylation of Ser311 on SPHK1 by ERK1/2, reversed by PP2A, causes plasma membrane targeting and activation of SPHK1. SPHK1 is best known as a survival, or anti-apoptosis, enzyme with additional positive effects on cell motility and proliferation resulting from the production of S1P. In addition, SPHK1-derived S1P activates endothelium, regulating endothelial barrier homeostasis, primes neutrophils, activates macrophages and promotes phagosome maturation, and increases immune cell motility and function. While some of the actions of SPHK2-derived S1P overlap those of SPHK1, SPHK2 may promote, rather than prevent, apoptosis.
Ceramide Actions
Ceramide is a bioactive lipid which regulates many cell functions, including apoptosis, proliferation, and differentiation. Its biological effects depend on its concentration, the time frame of activation, and the activation or differentiation status of the cell. In addition, ceramide may be produced in one membrane site and trafficked to others, e.g., from the plasma membrane to the mitochondrial membrane.4 Ceramide signals along several pathways, including ceramide-activated protein kinases (e.g., PKC and MEK isoforms) and protein phosphatases (e.g., PP1 and PP2A). This indicates that there is no general pathway of ceramide action, that the specific effects must be evaluated for each cellular situation.
Ionizing radiation-induced ROS activate PKCδ, which phosphorylates ASMase on Ser508 and causes the relocation of ASMase from lysosomes to the plasma membrane, as shown in Figure 2.5 Activated ASMase catalyzes the release of ceramide from lipid raft-associated sphingomyelin (SM) within minutes; additional ceramide production occurs hours later, when, in response to DNA damage, the de novo synthesis pathway is activated. More specifically, DNA damage induces proteasome-dependent processing of CerS1, followed by the translocation of the modified enzyme from the ER to the Golgi and increased ceramide production.6 Within the plasma membrane, the production of ceramide in lipid rafts drives the coalescence of multiple small rafts into ceramide-enriched membrane platforms.7 Within these platforms, ceramide may slowly flip between the inner and outer leaflets of the lipid bilayer and be accessible to intracellular molecules. Ionizing radiation, as well as other forms of stress, activate the SAPK/JNK pathways.8 Specifically, both JNK1 and JNK2 are activated by MAPK8 and MAPK9, which phosphorylate nuclear transcription factors, including c-Jun, Fos, JunB, and ATF2. Also, the JNKs target Bcl-2 family members associated with mitochrondria, driving apoptosis. In addition, ceramide, induced by stresses including radiation, inactivates the PI3K/Akt/Bad pathway, which also facilitates apoptosis.9
Sphingosine 1-Phosphate Effects
S1P was first thought to have its effects intracellularly, acting as a second messenger, interacting with and modulating the activities of specific target proteins. While this certainly happens,10 most current research focuses on the signaling of S1P as a secreted ligand, activating G-protein coupled receptors in an autocrine or paracrine fashion. These receptors were initially identified as EDG (endothelial differentiation gene) receptors and were orphan receptors. With the identification of S1P as a ligand for five of the EDG receptors, these have been renamed: S1P1 (EDG1), S1P2 (EDG5), S1P3 (EDG3), S1P4 (EDG6), and S1P5 (EDG8). S1P1 and S1P3 were first isolated from endothelial cells, while S1P2 was first found on rat brain and vascular smooth muscle cells, S1P4 was found on dendritic cells and S1P5 on rat PC12 (prostate cancer) cells. The five S1P receptors share high sequence identity with the cannabinoid and lysophosphatidic receptors, which are also G-protein coupled receptors for lipid ligands. Through these receptors, S1P regulates cell proliferation, differentiation, stress fiber formation, cell motility and migration, and cell survival.11
Perhaps one of the most exciting effects of S1P relates to its action on lymphocyte trafficking. The concentration of S1P in lymphoid tissues is normally low compared with that of the lymph. Lymphocytes within lymphoid tissues respond to this gradient, through the S1P1 receptor, by migrating from the tissue into the lymph. If the S1P levels within lymphoid nodes are elevated, by inhibition of S1P lyase, inflammation, or by the addition of stable S1P analogs, then lymphocyte egress is blocked. This greatly reduces the number of circulating lymphocytes and diminishes their ability to participate in the immune response. S1P analogs include SEW2871 , FTY720 , and (S)-FTY720-phosphonate. Because of its ability to reduce lymphocytic trafficking, FTY720 is effective in the treatment of multiple sclerosis.
S1P vs. Ceramide
Since ceramide is readily converted to sphingosine, which in turn can give rise to the potent mediator S1P, one might ask if S1P mediates any of the pro-apoptotic actions of ceramide. In fact, ionizing radiation initially downregulates sphingosine kinase 1, impairing the production of S1P.12 Moreover, added S1P has been shown to be a radioprotectant, preventing oocyte apoptosis and male sterility in irradiated mice.13-15 Isolated, proliferating endothelial cells, when irradiated, undergo an early premitotic apoptosis that is dependent on ceramide production in many cells, followed by a delayed death resulting from DNA damage in other cells. S1P protects cells from ceramide-dependent apoptosis but not from DNA damage-induced mitotic death.16 Also, mice maintained on S1P analogs are significantly protected against radiation-induced lung injury.17 It should be noted that these effects are seen over a 6 week period and appear to rely on altered gene expression in response to S1P analogs. Signaling via S1P1, S1P2, and S1P3, the analogs decrease vascular leak through several effects on the cytoskeletal and adhesive properties of endothelial cells.17 In addition, over this prolonged period, radiation increases the expression of both sphingosine kinase isoforms, perhaps suggesting the existence of a delayed protective feedback loop. Taken together, these studies suggest that intervention through S1P is an attractive approach to ameliorating the ceramide-dependent effects of ionizing radiation.
References
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