Second, glycine is added to the C-terminal of γ-glutamylcysteine. This condensation is catalyzed by
glutathione synthetase.
While all animal cells are capable of synthesizing glutathione, glutathione synthesis in the liver has been shown to be essential. GCLC
knockout mice die within a month of birth due to the absence of hepatic GSH synthesis.[4][5]
The unusual gamma amide linkage in glutathione protects it from hydrolysis by peptidases.[6]
Occurrence
Glutathione is the most abundant non-protein
thiol (R−SH-containing compound) in animal cells, ranging from 0.5 to 10 mmol/L. It is present in the
cytosol and the
organelles.[6] In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH), with the remainder in the disulfide form (GSSG).[7] 80-85% of cellular GSH is in the cytosol and 10-15% is in the
mitochondria.[8]
Systemic availability of orally consumed glutathione has poor bioavailability because the tripeptide is the substrate of
proteases (peptidases) of the
alimentary canal, and due to the absence of a specific carrier of glutathione at the level of cell membrane.[11][12] The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels.[13] The patented compound RiboCeine has been studied as a supplement that enhances production of glutathione which helps mitigate hyperglycemia.[14][15]
Biochemical function
Glutathione exists in reduced (GSH) and oxidized (
GSSG) states.[16] The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular
oxidative stress[17][8] where increased GSSG-to-GSH ratio is indicative of greater oxidative stress.
GSH protects cells by neutralising (reducing)
reactive oxygen species.[19][6] This conversion is illustrated by the reduction of peroxides:
2 GSH + R2O2 → GSSG + 2 ROH (R = H, alkyl)
and with free radicals:
GSH + R• → 1/2 GSSG + RH
Regulation
Aside from deactivating radicals and reactive oxidants, glutathione participates in thiol protection and redox regulation of cellular thiol proteins under oxidative stress by protein S-glutathionylation, a redox-regulated post-translational thiol modification. The general reaction involves formation of an unsymmetrical disulfide from the protectable protein (RSH) and GSH:[20]
RSH + GSH + [O] → GSSR + H2O
Glutathione is also employed for the
detoxification of
methylglyoxal and
formaldehyde, toxic metabolites produced under oxidative stress. This detoxification reaction is carried out by the
glyoxalase system.
Glyoxalase I (EC 4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoylglutathione.
Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-lactoylglutathione to glutathione and
D-lactic acid.
It maintains exogenous antioxidants such as
vitamins C and
E in their reduced (active) states.[21][22][23]
Metabolism
Among the many metabolic processes in which it participates, glutathione is required for the biosynthesis of
leukotrienes and
prostaglandins. It plays a role in the storage of cysteine. Glutathione enhances the function of
citrulline as part of the
nitric oxide cycle.[24] It is a
cofactor and acts on
glutathione peroxidase.[25] Glutathione is used to produce S-sulfanylglutathione, which is part of
hydrogen sulfide metabolism.[26]
The content of glutathione in
must, the first raw form of wine, determines the
browning, or caramelizing effect, during the production of
white wine by trapping the
caffeoyltartaric acid quinones generated by enzymic oxidation as
grape reaction product.[32] Its concentration in wine can be determined by UPLC-MRM mass spectrometry.[33]
^Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (October 2003). "The changing faces of glutathione, a cellular protagonist". Biochemical Pharmacology. 66 (8): 1499–1503.
doi:
10.1016/S0006-2952(03)00504-5.
PMID14555227.
^Scholz RW, Graham KS, Gumpricht E, Reddy CC (1989). "Mechanism of interaction of vitamin E and glutathione in the protection against membrane lipid peroxidation". Annals of the New York Academy of Sciences. 570 (1): 514–517.
Bibcode:
1989NYASA.570..514S.
doi:
10.1111/j.1749-6632.1989.tb14973.x.
S2CID85414084.
^Vallverdú-Queralt A, Verbaere A, Meudec E, Cheynier V, Sommerer N (January 2015). "Straightforward method to quantify GSH, GSSG, GRP, and hydroxycinnamic acids in wines by UPLC-MRM-MS". Journal of Agricultural and Food Chemistry. 63 (1): 142–149.
doi:
10.1021/jf504383g.
PMID25457918.