Antioxidants are needed in the cell to detox harmful substances. The oxidative phophorylation or sunlight produce reactive oxygen species in the body. These are oxygen containing molecules, which are in an ‘unbalanced’ state biochemically. They react quickly with their sorroundings and thereby cause damage. They can react with lipids or proteins and damage them.
Antioxidants help neutralize these reactive oxygen species. Toxins can also cause harm and are detoxed by antioxidants. Glutathione is a very important antioxidant. It is synthesized from the amino acids glycine, cysteine and glutamate. Cysteine can be produced with homocysteine from the methylation cycle.
Glutathione can recycle other antioxidants like vitamin C (1), vitamin E (2) and coenzyme Q10 (3).
Vitamin C is important for the energy metabolism because it is required for carnitine synthesis. Carnitine transports long-chained and middle-chained fatty acids into the mitochondria. Fatty acids can only be oxidized in the mitochondria so carnitine is required to produce acetyl-CoA from fatty acids.
Carnitine can also increase the function of the pyruvate dehydrogenase because it binds acetyl-CoA:
Carnitine+ Acetyl-CoA-> Acetyl-Carnitine+ CoA-SH
High acetyl-CoA levels inhibit the pyruvate dehydrogenase and carnitine reduced acetyl-CoA and releases CoA-SH which can then be used to again as a cofactor in the pyruvate dehydrogenase (4).
Coenzyme Q10 is a cofactor in the oxidative phosphorylation and low levels can reduce the production of ATP. Vitamin E has antioxidant functions and might be relevant for maintaining adenosylcobalamin levels in the cell (5).
Glutathione S-transferase mutations
Apart from the enzyme glutathione peroxidase, glutathione can also detox via glutathione S-transferase. Glutathione S-transferase (GST) is an enzyme that binds glutathione to xenobiotics (‘carcinogens, drugs, environmental pollutants, food additives, hydrocarbons, and pesticides’(6)), so they can then be excreted/detoxed. The activity of glutathione-S-transferase depends on glutathione synthesis by the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase.
There are mutations in the glutathione S-transferase gene (GSTM1, GSTT1, GSTP1) which can lead to reduced function of the glutathione S-transferase enzymes (7). Mutations that lead to non-functional glutathione S-transferase enzymes might be associated with lower levels of vitamin C (8).
Glutathione S-transferase activity depends on glutathione levels in the cell and good glutathione synthesis and regeneration might be relevant for GST to function properly. Especially people with a mutation might need sufficient levels of glutathione.
Because glutathione detoxes xenobiotics, low glutathione may be related to an intolerance of drugs, food additives etc. Detoxing these substances can reduce glutathione status and that in turn impacts the energy metabolism because of lower levels of vitamin C, E, Q10, leading to symptoms.
Rich Van Konynenburg, a researcher that worked on ME/CFS, thought that glutathione depletion could be one of the core issues of ME/CFS (more information on his theories here).
Possibly Relevant Cofactors
Vitamin B2 and B3 might be important for glutathione becasue their active forms FAD and NADPH are cofactors in the glutathione reductase. The glutathione reductase (GSSGR) recycles oxidized glutathione.
Vitamin B3/Niacin might also be important for producing glutathione. NAD+ is a cofactor in the enzyme S-adenosylhomocysteine hydrolase (SAHH), which converts S-adenosylhomocysteine to homocysteine (9). Too high homocysteine can increase the risk for certain diseases, but a certain amount of homocysteine is important for glutathione synthesis. Homocysteine can produce cysteine for glutathione synthesis.
Magnesium is needed in all ATP-dependent reactions. Magnesium binds to ATP and the Mg-ATP complex is then biolocally active (10). Two steps in the glutathione synthesis use ATP, the methionine adenosyltransferase and the glutamate cysteine ligase.
Vitamin D can increase glutathione synthesis and regeneration (11).
Here the pathway of glutathione synthesis, with these cofactors.
Low glutathione levels can impact the energy metabolism by leading to less recycling of vitamin C, E and Q10. This can reduce functions like vitamin C-dependent carnitine synthesis, which is needed for fatty acid oxidation and increases pyruvate dehydrogenase activity or Q10-dependent ATP production in the oxidative phosphorylation. Low glutathione can also reduce the detox capacity of the body.
Gene mutations in the glutathione S-transferase were associated with lower vitamin C levels, and this could indicate an increased need to support glutathione status, in my opinion. A few cofactors might support glutathione production and recycling.