In the methylation cycle, the homocysteine molecular pool is like a splitting of the path. Homocysteine can either regenerate methionine or produce cysteine, which can be used to make glutathione, a critical detoxification and antioxidant molecule. When trying to reduce inflammation, the requirements for glutathione increase. Therefore, when there is extra inflammation, the body redirects more homocysteine supply toward the production of glutathione. This causes less homocysteine to regenerate back into methionine.

Interestingly, there are two paths for the regeneration of homocysteine to methionine. One path uses betaine-homocysteine methyltransferase (BHMT), which depends on betaine. The other path uses folate, found in many plants, and B12, a vitamin that is mostly found in meats, eggs, and dairy.

One of the enzymes that controls the folate aspect of this cycle is methylenetetrahydrofolate reductase (MTHFR). Inhibition of this enzyme limits the efficient regeneration of methylation from homocysteine. Some people spend a lot of effort trying to increase MTHFR function.

However, the limitation may happen for a useful purpose. As mentioned, the limitation of MTHFR allows more homocysteine to go toward cysteine. This cysteine helps to produce more glutathione, which assists with reducing inflammation. Limiting MTHFR may be a way the body controls inflammation and alters methylation patterns to regulate metabolism.

For multiple reasons, redirecting homocysteine toward cysteine production might be so important that the body limits more than just the MTHFR enzyme. Many other aspects concerning the use of folate in the methylation cycle also change. For example, there are over six different disorders of folate transport and metabolism (1).

The body also inhibits other enzymes that affect the generation of methionine from homocysteine. Amazingly, the construction of multiple enzymes in the methylation cycle is in such a way that excess reactive oxygen species can damage the function of these enzymes.

For example, reactive oxygen species can inhibit betaine homocysteine methyltransferase (BHMT) (2) (3) as well as methionine synthase (MS) (4). These enzymes are critical for efficient methylation cycle function. Limiting them slows down the methylation cycle even further.

Interestingly, reactive oxygen species can also reduce the availability of 5-methyltetrahydrofolate (5-MTHF) used by the MTHR enzyme to regenerate homocysteine into methionine. Research found that reactive oxygen species superoxide and hydrogen peroxide decreased the uptake of 5-MTHF by cells significantly (5). Other researchers also found reactive oxygen species generation may affect the development of 5-MTHF deficiency (6). Less availability of 5-MTHF significantly slows down the methylation cycle.

Additionally, there are genetic changes that reduce the function of the MTHFR enzyme. Since reactive oxygen species and genetic changes can inhibit multiple enzymes designed to regenerate methionine from homocysteine, this means the body wants to slow down the methylation cycle when there are too many reactive oxygen species and inflammation.

Furthering this point, reactive oxygen species also limit methylation by directly damaging DNA. Damage to DNA from the hydroxyl radical, a powerful potential source of inflammation, can interfere with the ability to methylate the damaged DNA (7).

Critically, reactive oxygen species can inhibit the activity of many other enzymes besides just the enzymes involved in methylation. This ability to inhibit many enzymes in this way is likely a purposeful design that allows the body to change enzyme functions depending on the number of reactive oxygen species nearby. This permits the cells to precisely adjust many functions according to the amount of inflammation that is happening.

For example, because of reactive oxygen species, some enzymes temporarily form disulfide bonds, which reduce enzyme activity (8). Reactive oxygen species can also inhibit GAPDH and block glycolysis (8). This glycolysis inhibition limits glucose metabolism. Slowing down the metabolism of glucose can limit the creation of more reactive oxygen species. This is a useful redirect if there are already too many reactive oxygen species inside the cell. There are further discussions of potentially purposeful redirects like this in Chapter 6.