Glutathione

Antioxidant in plants, animals, fungi, and some bacteria and archaea.

- Glutathione

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Cysteine

Semiessential proteinogenic amino acid with the formula HOOC-CH-(NH2)-CH2-SH.

Cysteine synthesis: Cystathionine beta synthase catalyzes the upper reaction and cystathionine gamma-lyase catalyzes the lower reaction.

Figure 2: Cystine (shown here in its neutral form), two cysteines bound together by a disulfide bond

Its antioxidant properties are typically expressed in the tripeptide glutathione, which occurs in humans and other organisms.

Antioxidant

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals and chain reactions that may damage the cells of organisms.

Structure of the metal chelator phytic acid

The structure of the antioxidant vitamin ascorbic acid (vitamin C)

The free radical mechanism of lipid peroxidation

Decameric structure of AhpC, a bacterial 2-cysteine peroxiredoxin from Salmonella typhimurium

Substituted phenols and derivatives of phenylenediamine are common antioxidants used to inhibit gum formation in gasoline (petrol).

Fruits and vegetables are good sources of antioxidant vitamins C and E.

To balance oxidative stress, plants and animals maintain complex systems of overlapping antioxidants, such as glutathione.

Oxidative stress

Imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.

Reactive oxygen species

Reactive oxygen species (ROS) are highly reactive chemicals formed from O2.

Major cellular sources of ROS in living non-photosynthetic cells. From a review by Novo and Parola, 2008.

Free radical mechanisms in tissue injury. Free radical toxicity induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination).

Initiation of DNA demethylation at a CpG site. In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides (CpG sites), forming 5-methylcytosine-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 8-hydroxy-2'-deoxyguanosine (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits TET1 and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC.

Demethylation of 5-Methylcytosine (5mC) in neuron DNA. As reviewed in 2018, in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).

Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a sulfur-containing tripeptide called glutathione.

Tripeptide

Peptide derived from three amino acids joined by two or sometimes three peptide bonds.

In terms of scientific investigations, the dominant tripeptide is glutathione (γ- L -Glutamyl- L -cysteinylglycine), which serves many roles in many forms of life.

Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.

LTA4 Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4.

LTC4 is a cysteinyl leukotriene, as are D4 and E4.

Eicosanoid synthesis. (Leukotrienes at right.)

LTF4, like LTD4, is a metabolite of LTC4, but, unlike LTD4, which lacks the glutamic residue of glutathione, LTF4 lacks the glycine residue of glutathione.

NMDA receptor

Glutamate receptor and ion channel found in neurons.

Stylized depiction of an activated NMDAR. Glutamate is in the glutamate-binding site and glycine is in the glycine-binding site. The allosteric site, which modulates receptor function when bound to a ligand, is not occupied. NMDARs require the binding of two molecules of glutamate or aspartate and two of glycine

Cartoon representation the human NMDA receptor. Each subunit is individually rainbow colored.

Figure 2: Transmembrane region of NR1 (left) and NR2B (right) subunits of NMDA receptor.

NR2 subunit in vertebrates (left) and invertebrates (right). Ryan et al., 2008

The timecourse of GluN2B-GluN2A switch in human cerebellum. Bar-Shira et al., 2015

L -Glutamic acid (glutamate), the major endogenous agonist of the main site of the NMDAR.

Glycine, the major endogenous agonist of the glycine co-agonist site of the NMDAR.

Figure 6: Chemical structure of neramexane, second generation memantine derivative.

N-Methyl- D -aspartic acid (NMDA), a synthetic partial agonist of the main site of the NMDAR.

Ketamine, a synthetic general anesthetic and one of the best-known NMDAR antagonists.

Figure 7: Nitroglycerin donate ONO2 group that leads to second generation memantine analog, nitromemantine.

Figure 4: The chemical structures of MK-801, phencyclidine and ketamine, high affinity uncompetitive NMDA receptor antagonists.

Figure 5: Chemical structures of memantine (right) and amantadine (left).

Figure 8: Structure activity relationship (SAR) of amantadine and related compounds

However, hypofunction of NMDA receptors (due to glutathione deficiency or other causes) may be involved in impairment of synaptic plasticity and could have other negative repercussions.

Glutathione S-transferase

A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5).

Glutathione S-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to xenobiotic substrates for the purpose of detoxification.

Thiol

Any organosulfur compound of the form R−SH, where R represents an alkyl or other organic substituent.

Synthesis of thiophenolate from thiophenol

The catalytic cycle for ribonucleotide reductase, demonstrating the role of thiyl radicals in producing the genetic machinery of life.

Thiyl intermediates also are produced by the oxidation of glutathione, an antioxidant in biology.

Drug metabolism

Metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems.

Phases I and II of the metabolism of a lipophilic xenobiotic.

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid.