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

• 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