Glutathione synthesis and

Yoshida, K., J. Hirokawa, S. Tagami, Y. Kawakami, Y. Urata, and T. Kondo. 1995. Weakened cellular scavenging activity against oxidative stress in diabetes mellitus Regulation of glutathione synthesis and efflux. Diabetologia. 38 201-10. 

Castagne V, Cuenod M, Do KQ. 2004a. An animal model with relevance to schizophrenia Sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development. Neuroscience 123 821-834. 

The hormonal regulation of GCS expression has special physiological relevance. Phenylephrine, glucagon or dibutyryl cAMP inhibit GCS activity, which decreases glutathione synthesis and leads to glutathione depletion in rat hepatocytes [26,27]. The loss of GCS activity induced by these stress hormones is mediated by phosphorylation of the catalytic GCS subunit due to activation of protein kinase A, protein kinase C or Ca -calmoduhn kinase [28]. Consequently, the stress response diminishes GSH synthesis, which may increase the availability of cysteine for the synthesis of stress proteins [14]. 

Fig. 37.6. 7-Glutamyl cycle. In cells of the intestine and kidney, amino acids can be trans-pwrted across the cell membrane by reacting with glutathione (7-glutamyl-cysteinyl-glycine) to form a 7-glutamyl amino acid. The amino acid is released into the cell, and glutathione is resynthesized. However, the major role of this cycle is glutathione synthesis, and many tissues lack the transpieptidase and 5-oxo-prohnase activities.

Cysteine [52-90 ] is a thiol-bearing amino acid which is readily isolated from the hydrolysis of protein. There ate only small amounts of cysteine and its disulfide, cystine, in living tissue (7). Glutathione [70-18-8] contains a mercaptomethyl group, HSCH2, and is a commonly found tripeptide in plants and animals. Coenzyme A [85-61-0] is another naturally occurring thiol that plays a central role in the synthesis and degradation of fatty acids. 

Gotoh, N., Graham, A., Niki, E. anel Darley-Usmar, V.M. (1993). Inhibition of glutathione synthesis increases the toxicity of oxidised LDL to human monoctites and macrophages. Biochem. J. 296, 151-154. 

Williamson, J.M., Boettcher, B. and Meister, A. (1982). Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis. Proc. Natl Acad. Sci. USA 79, 6246-6249. 

The most important product of the hexose monophosphate pathway is reduced nicotinamide-adenine dinucleotide phosphate (NADPH). Another important function of this pathway is to provide ribose for nucleic acid synthesis. In the red blood cell, NADPH is a major reducing agent and serves as a cofactor in the reduction of oxidized glutathione, thereby protecting the cell against oxidative attack. In the syndromes associated with dysfunction of the hexose monophosphate pathway and glutathione metabolism and synthesis, oxidative denaturation of hemoglobin is the major contributor to the hemolytic process. 

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

Defects in the Hexose Monophosphate Pathway and Glutathione Metabolism and Synthesis... 

Lu, S.C. (1999) Regulation of hepatic glutathione synthesis current concepts and controversies. FASEB Journal, 13, 1169-1183. 

Azathioprine is a pro-drug as it is converted by interaction, mainly in red blood cells, with nucleophils like glutathione to its active form 6-mercaptopurine after which 6-mercaptopurine nucleotides are generated that inhibit purine synthesis and can lead to DNA damage by intercalation. Although the activity of 6-mercaptopurine is well understood there are indications that azathioprine itself contributes to an enhanced immunosuppressive activity. 

---