Význam
Conversion of prostaglandin H2
- A metabolite of arachidonic acid into prostaglandins D2 and E2 by endoperoxide isomerase [1]
GSH inhibits infection
- By the influenza virus [1]
Glutathione peroxidase - GPx
- Catalyzed by the reaction catalyzed by the reduced form of glutathione (GSH)
- By reacting with hydrogen peroxide or lipid peroxides
- While playing a role in the detoxification of these molecules by creating a glutathione bridge with another glutathione molecule (GSSG) form
- H2O2 is detoxified by catalase and glutathione peroxidase
- Glutathione redox cycle plays a key role in the reduction of intracellular hydroperoxides
- GPx belongs to the class of selenocysteine compound
- It binds four atoms of selenium
- Provides the catalytic activity of glutathione peroxidase
- It needs glutathione as a co-substrate
- www.intechopen.com/books/glutathione-system-and-oxidative-stress-in-health-and-disease/glutathione-peroxidase-in-health-and-diseases
- Glutathione peroxidase (GSH-Px; E.C. 1.11.1.9)
- Cytosolic enzyme
- Reduction of hydroperoxides
- In erythrocytes, GSH-Px is the most effective antioxidant against oxidant stress
- Has some important functions in phagocytic cells
- Most effective enzyme in endothelial cells and especially in the lung !!!
- Cca 60–75% of enzyme activity is found in the eukaryotic cell cytoplasm
- Cca 25–40% activity is found in mitochondria
- The most common enzyme activity is clear in erythrocytes and liver
- GPx is the most important enzyme that protects lipids from peroxidation at intracellular distance
- Maintains the structure and function of the cell
www.intechopen.com/books/glutathione-system-and-oxidative-stress-in-health-and-disease/glutathione-peroxidase-in-health-and-diseases
- GSH-Px is also involved in the detoxification of xenobiotics
- Provides the most vital defense against the peroxidative damage of biological membranes in mammalian cells
- Glutathione peroxidase, catalase, and superoxide dismutase together
- Form a common system aimed at protecting the cell from peroxidant molecules
- Inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration.
- selenium deficiency increases susceptibility to ferroptotic processes and other programmed cell death pathways due to a decrease in GPx activity
- Reduction of peroxides, which inactivate vasodilating NO
- Decomposition of S-nitrosoglutathione (GSNO)
- Important role in vascular homeostasis
- H202 difunduje přes membrány a reaguje přednostně se sloučeninami obsahujícími thiol, které iniciují redox signalizace.
cs.ulfsciences.com/nadph-oxidases-ros-signaling-gastrointestinal-tract-560408
Decreased GPx activity
- Causes hepatocellular degeneration and premature death of mice.
- Since many harmful conditions are known to directly disrupt the GPx
- Inhibition of ferroptosis may represent a suitable therapeutic approach to improve hepatocyte cell death.
- GPx is particularly vulnerable to the oxidative stress associated with hypertension.
www.intechopen.com/books/glutathione-system-and-oxidative-stress-in-health-and-disease/glutathione-peroxidase-in-health-and-diseases
GPx1 deficiency
- Led to endothelial dysfunction,
- Impaired angiogenesis,
- Increased infarction size and vascular permeability following ischemia/reperfusion injury
Glutathionylation of proteins
- Thioredoxin, ubiquitin-conjugating enzyme, and cytochrome c oxidase
- Plays an important role in cell physiology [1]
Glyoxalase system
- Converts methylglyoxal to d-lactate
- A pathway active in microorganisms [1]
Imunita
- Essential for the activation of T-lymphocytes and polymorphonuclear leukocytes
- As well as for cytokine production
- For mounting successful immune responses when the host is immunologically challenged [1]
Keeping sulfhydryl groups in proteins in the reduced state
- Funkce proteinů - tvar ve 3D cestou -S-S- vazeb !!!
Glutathion + NO
- Exposure of human neutrophils to NO
- Results in the conversion of intracellular GSH to GSNO
- Intracellular GSNO activates the hexose monophosphate shunt of the cells
- Since GSH concentration is millimolar in cells and NO concentration is less than micromolar
- It follows that the concentration of GSNO will always be small compared that of GSH.
- Addition to release of NO from GSNO in the presence of GSH
- Important pathway for GSNO decomposition is reaction with GSH to form glutathione conjugates
- Similar to those reported for the reaction of GSH with other electrophilic metabolites
- Major end product from this transformation is oxidized GSH, GSSG
- Amount formed is dependent on the availability of oxygen in the system
- Suggesting the possible involvement of radicals.
- NO was being released from GSNO in the presence of GSH
- GSH conjugation is believed to be one of the primary detoxification mechanisms in vivo.
www.pnas.org/content/93/25/14428
<2>Oxidace GSH2>
- Shifting the GSH/GSSG redox toward the oxidizing state activates several signaling pathways including
- protein kinase B,
- protein phosphatases 1 and 2A,
- Calcineurin = antivirový
- Nuclear factor ?B,
- C-Jun N-terminal kinase
- Apoptosis signal-regulated kinase 1
- Mitogen-activated protein kinase
- Thereby reducing cell proliferation and increasing apoptosis = antivirové...
Phospholipid hydroperoxide glutathione peroxidase (PLGSH-Px)
- Reduces membrane phospholipid hydroperoxides to alcohol
- Also contains the Se atom and is monomeric
- It is also a cytosolic enzyme
- PLGSH-Px provides protection against peroxidation of the membrane
- In cases where vitamin E, a membrane-bound antioxidant, is insufficient
- Glutathione peroxidase catalyzes detoxification of H2O2 and lipid peroxides by reduced glutathione.
- Thus, it protects membrane lipids and hemoglobin from oxidation of peroxides
Proliferace
- Adequate GSH concentrations are necessary for the proliferation of cells, including
- Lymphocytes
- Intestinal epithelial cells
Spermatogenesis and sperm maturation
Substrate for formaldehyde dehydrogenase
- Converts formaldehyde and GSH to S-formyl-glutathione
- Removal of formaldehyde (a carcinogen) is of physiological importance
- Because it is produced from the metabolism of:
- methionine,
- Choline,
- Methanol (alcohol dehydrogenase)
- Sarcosine (sarcosine oxidase)
- Xenobiotics (via the cytochrome P450-dependent monooxygenase system of the endoplasmic reticulum) [1]
Vitiligo
- Significant relationship between low GPx level and vitiligo.
Vychytávač volných radikálů
- The most important antioxidant molecule of intracellular environment
- GSH effectively scavenges free radicals and other reactive oxygen species
- Hydroxyl radical, lipid peroxyl radical, peroxynitrite, and H2O2
- Directly, and indirectly through enzymatic reactions
- GSH is oxidized to form GSSG
- Then reduced to GSH by the NADPH-dependent glutathione reductase
- Glutathione peroxidase (a selenium-containing enzyme)
- catalyzes the GSH-dependent reduction of H2O2 and other peroxides [1]
- Most abundant cytosolic thiol
- Important roles in the non-enzymatic antioxidant defence system
- Free radical scavenging activity
- ·OH, ·OOH, ·OCH3, ·OOCH3, ·OOCHCH2 and ·OOCCl3
- Reacts exclusively by H transfer
- With the exception of its reaction with ·OH there is only one important channel of reaction, yielding to the S-centered radical
- Exceptionally good as a OOH radical scavenger
- Comparable to 2-propenesulfenic acid
- Strong H bonding interactions found in the transition states, which involves the carboxylate moiety
- pubs.rsc.org/en/content/articlelanding/2011/ra/c1ra00474c#!divAbstract
Redoxní cyklus
- Glutathione, in reduced form (GSH), turns itself into oxidized glutathione (GSSG) form with creating disulfide bridge with another glutathione molecule
- While playing role in detoxification of these molecules by reacting with hydrogen peroxides or lipid peroxides, with the reaction catalyzed by the GPx enzyme
- For the maintenance of free radical detoxification in cell, GSSG needs to be converted back to the reduced form
- GSSG is converted to reduced glutathione form with GR enzyme by a reaction in which NADPH is used
GSH conjugates with NO
- To form an S-nitroso-glutathione adduct
- Cleaved by the thioredoxin system to release GSH and NO
- Recent evidence suggests that the targeting of endogenous NO is mediated by intracellular GSH
- Both NO and GSH are necessary for the hepatic action of insulin-sensitizing agents
- Indicating their critical role in regulating lipid, glucose, and amino acid utilization [1]
GSH reacts with various electrophiles, physiological metabolites
- Estrogen,
- Melanins,
- Prostaglandins,
- Leukotrienes
- Bromobenzene
- Acetaminophen
- To form mercapturates
- Initiated by glutathione-S-transferase (a family of Phase II detoxification enzymes) [1]
Indikace
- Glutathion se používá při
- Alzheimerově
- Parkinsonově chorobě
- šedém a zeleném zákalu
- alkoholizmu
- Prevenci stárnutí
- Astmatu
- Nádorových onemocněních
- Kardiovaskulárních chorobách (ateroskleróze a hypercholesterolemii)
- žloutenkách a onemocnění jater
- Snížené imunitě (včetně AIDS a chronickém únavovém syndromu)
- Ztrátě paměti
- Zánětech pohybového ústrojí
- Detoxikaci těžkých kovů
- Pro snížení toxického účinku některých léčiv (cisplatiny)
- www.uspesna-lecba.cz/glutathion/
Popisované účinky
- Zlepšuje cévní prokrvení všech orgánů
- Snižuje riziko vzniku trombóz
- Zlepšuje činnost a zvyšuje výkon srdce
- Potlačuje vznik a rozvoj nemocí trávicího traktu například žaludečních vředů, Crohnovy choroby, onemocnění slinivky ...
- Zvyšuje citlivost na inzulín
- Nefroprotektivní
- Zlepšuje stav nervového systému, zlepšuje průběh nervových i psychických onemocnění
- Zlepšuje stav arteriosklerotických změn (například mozkových cév)
- Neutralizuje toxické látky jako jsou těžké kovy, nejrůznější toxická farmaka, ale také následky elektromagnetického záření a UV záření
- Protinádorový účinek
- Prodlužuje život a chrání tělo před předčasným stárnutím
- L-Glutathion není toxický ani ve vysokých dávkách
- www.uspesna-lecba.cz/glutathion/
Význam glutathionu
- Concentrations of reduced glutathione (GSH) in most cell types highlights its vital and multifunctional roles in the control of various biological processes such as
- Detoxification of foreign and endogenous compounds,
- protein folding,
- Regeneration of vitamins C and E,
- Maintenance of mitochondrial function,
- Antiviral defense,
- Regulation of cellular proliferation, apoptosis,
- Immune response