Glutatione (GSH): significato

Author: Gianpiero Pescarmona
Date: 02/04/2022


Il Glutatione (GSH) è un tripeptide formato da glutamato, cisteina e glicina. La presenza del gruppo -SH gli permette sia di funzionare da anti-ossidante che da legante di numerose sostanze che, una volta coniugate con il GSH, vengono escrete.

Video Sul Glutatione 20 aprile 2022. (La mia parte inizia al minuto 22), organizzato dalla SIM

Testo preliminare sul GSH

Decadimento con l'età

Per comprendere appieno il significato biologico del GSH, non basta elencare le reazioni a cui prende parte, ma comprendere quale è l'ambiente che ne rende possibile la sintesi.

Il contenuto di informazione di ogni molecola del nostro organismo comprende anche la sommatoria di tutte le condizioni che ne rendono possibile la sintesi

Nel caso del GSH le condizioni sono:
La disponibilità nelle cellule di:

  • ATP
  • Mg ++

La disponibilità nel siero di:

  • glutamato (0.041/0.067, Glu+Gln 0.65/0.56)
  • cisteina (0.002/0.016)
  • glicina (0.244/0.315)

(Serum amino acid concentrations in aging men and women, 2003)

Le proprietà degli enzimi coinvolti

  • glutamato-cisteina ligasi (GCL): km ATP : 0.26 - 4.47, glutamate: 0.7/3.5, cysteine: 0.1 - 0.8
  • glutatione sintasi (GS). km ATP: 0.02/2.66 gamma-L-Glu-L-Cys: 0.34/0.66, Glicina: 0.36/2.52

Cellular GSH homeostasis and GSH-dependent reactions. Intracellular GSH balance is maintained by de novo synthesis, regeneration from GSSG, and extracellular GSH uptake. In transport epithelial cells, such as enterocytes, γ -glutamyl transferase ( γ -GT) and dipeptidase (DP) catalyzed the hydrolysis of extracellular GSH to its constituent amino acids, glutamate, cysteine and glycine. Additionally, intestinal epithelial cells can import intact GSH from the lumen via specifi c plasma membrane transporters. Cytosolic synthesis of GSH takes place in two ATP-dependent reactions catalyzed by glutamate-cysteine ligase (GCL) and glutathione synthase (GS). The intracellular GSH pool, present in millimolar concentrations, is involved in various GSH-dependent reactions. Compartmentation of GSH within the mitochondria, nucleus or endoplasmic reticulum creates distinct and independently regulated subcellular redox pools. As part of the antioxidant defence system, GSH participates in conjugation reactions catalyzed by glutathione-S-transferases (GSTs), in the reduction of hydrogen peroxide (H O ) and lipid hydroperoxides (LOOH) catalyzed by glutathione peroxidases (Gpxs), and the reduction 2 2 of protein-disulfi des (PrSSG) catalyzed by glutaredoxins (Grxs). The reduction of glutathione disulfi de (GSSG) by glutathione reductase (GR) in the GSH redox cycle regenerates GSH. GSSG reduction occurs at the expense of NADPH, produced from the pentose phosphate pathway (PPP) from glucose oxidation.

GSH synthesis regulation

Regulation of glutathione synthesis, 2008(GCL).

  • Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.

Dimorfismo sessuale

Sexual_dimorphism_in_glutathione_metabolism, 2020


The Role of Glutathione in Protecting Against the Severe Inflammatory Response Triggered by COVID-19, 2020: Scite

2022-04-19T08:57:15 - Gianpiero Pescarmona

spermatozoa e GSH

2022-04-12T21:53:37 - Gianpiero Pescarmona

GSH glucocorticoids

2022-04-12T21:53:19 - Gianpiero Pescarmona


2022-04-03T21:13:01 - Gianpiero Pescarmona

Evoluzione della molecola


Expanding the paradigm of thiol redox in the thermophilic root of life. 2013

BACKGROUND The current paradigm of intracellular redox chemistry maintains that cells establish a reducing environment maintained by a pool of small molecule and protein thiol to protect against oxidative damage. This strategy is conserved in mesophilic organisms from all domains of life, but has been confounded in thermophilic organisms where evidence suggests that intracellular proteins have abundant disulfides.
METHODS Chemical labeling and 2-dimensional gel electrophoresis were used to capture disulfide bonding in the proteome of the model thermophile Sulfolobus solfataricus. The redox poise of the metabolome was characterized using both chemical labeling and untargeted liquid chromatography mass spectrometry. Gene annotation was undertaken using support vector machine based pattern recognition.
RESULTS Proteomic analysis indicated the intracellular protein thiol of S. solfataricus was primarily in the disulfide form. Metabolic characterization revealed a lack of reduced small molecule thiol. Glutathione was found primarily in the oxidized state (GSSG), at relatively low concentration. Combined with genetic analysis, this evidence shows that pathways for synthesis of glutathione do exist in the archaeal domain.
CONCLUSIONS In observed thermophilic organisms, thiol abundance and redox poise suggest that this system is not directly utilized for protection against oxidative damage. Instead, a more oxidized intracellular environment promotes disulfide bonding, a critical adaptation for protein thermostability.
GENERAL SIGNIFICANCE Based on the placement of thermophilic archaea close to the last universal common ancestor in rRNA phylogenies, we hypothesize that thiol-based redox systems are derived from metabolic pathways originally tasked with promoting protein stability.

Ammonia oxidation is not required for growth of Group 1.1c soil Thaumarchaeota. 2013

Traditionally, archaea were considered to be extremophiles, inhabiting ecosystems with very low pH, low oxygen concentration, high temperature or high salt concentration.

Something old, something new, something borrowed; how the thermoacidophilic archaeon Sulfolobus solfataricus responds to oxidative stress. 2009

Although Archaea are thought not to have glutamate cysteine ligase (GshA) or glutathione synthase (GshB), key enzymes in glutathione synthesis, there is a report of a putative gamma-glutamylcysteine ligase (GshA) from the archaea Methanosphaera stadtmanae (che in realta' sembra piu' moderno dell'omologo umano)

2022-04-02T22:42:29 - Gianpiero Pescarmona

Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate such as leukotriene C4 (PubMed:21447318).

Does not cleaves gamma-glutamyl compounds such as gamma-glutamyl leucine (PubMed:21447318).

May also catalyze a transpeptidation reaction in addition to the hydrolysis reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:21447318).

Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses (PubMed:30842656).


G-protein coupled receptors and ligands that organize humoral immune responses. 2019

We will discuss our recent identification of geranylgeranyl-glutathione as a ligand for P2RY8.

Molto espresso in CD4+ e CD8+ (vedi)

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