Tetrahydrofolate

For many people, their DHF from the diet leads to adequate L-methylfolate levels, however, malabsorption, digestive and liver disease, as well as certain genetic enzyme polymorphisms, can result in an impaired ability to activate folic acid. This L-methylfolate deficiency results in symptoms and conditions including mental health disorders, cardiovascular disease, increased adiposity, reduced lean body mass, birth defects and an increased risk for certain cancers.

Folate metabolism is required for optimal methylation. Methylation is a major pathway to focus on in understanding autoimmune and neurological diseases such as multiple sclerosis, seizure disorders, dementia, chronic fatigue syndrome, lupus, depression, anxiety and autism spectrum disorders. Methylation is responsible for making, maintaining and repairing DNA.

The Methylation Cycle is a biochemical pathway that manages or contributes to a wide range of biochemical functions: detoxification, supporting DNA (turning genes on and off), producing energy, reducing inflammation, synthesising neurotransmitters, homocysteine metabolism, protein methylation, phase 2 liver detoxification and supporting immune function. Inadequate methylation capacity can lead to birth defects, depression, cognitive decline and cancer. Impaired methylation has even been associated with autism. Support of methylation markers has been associated with rapid return of speech, improvement of behaviour in ADD and ADHD spectrums.

Tetrahydrofolate is the basic, reduced form of folate from which other forms of reduced folate are made.

Active and Inactive Forms of Folate:

Dihydrofolate (DHF) is the dietary form of folate, whilst folic acid is the synthetic form of folate used in supplements and to fortify the food supply. These forms of folate are not biologically active; they must undergo enzymatic transformation to L-methylfolate in order to be used by cells. L-methylfolate, unlike the other folates, is able to cross the blood-brain barrier for use in the CNS. The conversion of dihydrofolate (DHF) and folic acid to L-methylfolate occurs through a three or four step process:

1. Folic acid is converted to DHF by the dihydrofolate reductase enzyme (DHFR)

2. DHF is then converted to tetrahydrofolate (THF)

3. THF is converted to 5,10-methyleneTHF

4. 5,10-methyleneTHF is converted to L-methylfolate by the methyltetrahydrofolate reductase enzyme (MTHFR).