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Glutathione is not an essential nutrient since it can be synthesized from the amino acids L-cysteine, L-glutamic acid and glycine. The sulfhydryl (thiol) group (SH) of cysteine serves as a proton donor and is responsible for the biological activity of glutathione. Provision of this amino acid is the rate-limiting factor in glutathione synthesis by the cells since cysteine is relatively rare in foodstuffs. Furthermore, if released as the free amino acid, cysteine is toxic and spontaneously catabolized in the gastrointestinal tract and blood plasma.[4]

Glutathione is synthesized in two adenosine triphosphate-dependent steps:

First, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase (a.k.a. glutamate cysteine ligase, GCL). This reaction is the rate-limiting step in glutathione synthesis.
Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase.
Animal and insect glutamate cysteine ligase (GCL) is a heterodimeric enzyme composed of a catalytic (GCLC) and modulatory (GCLM) subunit. GCLC constitutes all the enzymatic activity, whereas GCLM increases the catalytic efficiency of GCLC. Mice lacking GCLC (i.e., all de novo GSH synthesis) die before birth.[5] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.[6][7][8]

While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential. Following birth, mice with genetically-induced loss of GCLC (i.e., GSH synthesis) only in the liver die within 1 month of birth.[9]

The plant glutamate cysteine ligase (GCL) is a redox sensitive homodimeric enzyme, conserved in the plant kingdom.[10] In an oxidizing environment intermolecular disulfide bridges are formed and the enzyme switches to the dimeric active state. The mid-point potential of the critical cysteine paire is - 318 mV. In addition to the redox dependent control is the plant GCL enzyme feedback inhibited by GSH.[11] GCL is exclusively located in plastids and glutathione synthetase is dual-targeted to plastids and cytosol, thus are GSH and gamma-glutamylcysteine exported from the plastids.[12] Both glutathione biosynthesis enzymes are essential in plants, knock-outs of GCL and GS are embryo and seedling lethal.[13]

The biosynthesis pathway for glutathione is found in some bacteria, like cyanobacteria and proteobacteria, but is missing in many other bacteria. Most eukaryotes synthesize glutathione, including humans, but some do not, such as Leguminosae, Entamoeba, and Giardia. The only archaea that make glutathione are halobacteria