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To understand the significance of any form of supplementation in a health care setting, practitioners should be aware of or investigate the biochemistry of any particular pathway that that supplement is involved in. To help practitioners understand more about the significance of the role of the methylenetetrahydrofolate reductase (MTHFR) gene in health and disease, this article summarizes relevant findings amassed over many years.  It details what is actually known about the evolution and metabolism of homocysteine, particularly with respect to the activity of the MTHFR gene. It also summarizes the pros and cons of various supplementation strategies and treatments.

About the MTHFR Gene

The MTHFR gene encodes the enzyme methylenetetrahydrofolate reductase (MTHFR). MTHFR reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major methyl group donor involved  in the re-methylation of homocysteine to methionine (see below). It is considered that lowered MTHFR activity, due to inheritance of a number of common genetic variants, predisposes to increased risk for development of several disorders including cardiovascular disease, thrombosis, neural tube defects, pregnancy complications, certain cancers, Alzheimer disease and even autism. But it is considered that it is elevated levels of the amino acid homocysteine that are more directly involved in the pathomechanism of these disorders rather than MTHFR mutations per se.

Genetics of MTHFR

Homocysteine levels can be elevated due to the inheritance of mutated MTHFR genes. Mutated MTHFR genes produce an enzyme, MTHFR that does not work properly, or insufficient enzyme to perform its function. Inheritance of a mutated MTHFR gene is the most common risk factor for elevated homocysteine levels.

Everyone inherits 2 MTHFR genes, one from each parent. It is usually when people inherit a mutant gene from both parents that MTHFR activity is significantly reduced. Inheritance of just one mutant MTHFR gene may not be associated with significant health problems.   

The most common MTHFR mutation is called the MTHFR C677T mutation, or the ‘thermolabile’ MTHFR  mutation. Another common mutation is called MTHFR A1298C. To have any detrimental effect, as indicated, mutations must be present in both copies of a person’s MTHFR genes that they inherit. Even when 2 MTHFR mutations are inherited, not all people will develop pathologically high homocysteine levels.

It is important to recognize that attempts to increase the expression of mutant MTHFR genes is quite contra-indicated, particularly in cases in which a dysfunctional enzyme is produced.

The mutants C677T and A1298C represent alterations in the sequence of DNA that encodes the enzyme. It is a straightforward laboratory test involving DNA sequencing of a person’s MTHFR genes that is used to determine the genetic status of a person’s MTHFR genes. Also, there are many other rarer mutant forms of the MTHFR gene that predispose to synthesis of a dysfunctional enzyme.[1]

Studies have shown that, rather than genetic typing for mutant MTHFR genes, determination of the level of homocysteine in the blood may be more helpful in predicting the likelihood of increases disease susceptibility.

What is Homocysteine?

Homocysteine is a non-coding amino acid that is generated naturally in the body. It is produced as a part of the cycle that permits the addition of a methyl group to DNA and other biological substances.

There are very many (around two hundred) amino acids known. Only twenty of them are used by the genetic code to make proteins. Of these twenty amino acids, eleven of them are able to be manufactured by the body. The other nine amino acids cannot be synthesised by the body, they have to be made available to the body from foods. Because of this requirement, these nine amino acids are referred to as essential amino acids. Methionine is one of the essential amino acids.

What is so Important about Methionine?

Methionine is an important amino acid because it is the body’s source of a methyl group -CH₃, an important chemical group that can be attached to DNA and other biological substances. Methyl groups are attached to the cytosine nucleotide (one of the four building blocks, C, T, G and A) of DNA. Attachment of a methyl group to DNA is called DNA methylation. Methylation of DNA plays a very important role in regulating the activity of genes. So, how does methionine contribute to DNA methylation?

The DNA Methylation Cycle

Methionine contains a methyl group, CH₃.  Firstly, ingested methionine is converted to S-adenosylmethionine (SAM) by an enzyme called methionine adenosyltransferase.

SAM is then able to transfer its methyl group to the nucleotide cytosine in DNA. As indicated, cytosine methylation plays an important role in regulation of gene expression. 

Transfer of methyl groups from SAM to DNA is brought about by a group of enzymes called methyltransferases. 

Following transfer of the methyl group from SAM to DNA, SAM is converted into S-adenosylhomocysteine (SAH). An enzyme called adenosylhomocysteinase then converts SAH to homocysteine.

Homocysteine, a toxic non-coding amino acid, is then converted back to methionine by reconstitution of its methyl group. To do this, a methyl group is added to homocysteine from 5-methyltetrahydrofolate, 5THF. The methyl group is transferred to homocysteine by an enzyme called methionine synthase. 

5THF is actually formed from a precursor molecule called 5,10-methylenetetrahydofolate, 5,10 methyleneTHF. This important conversion, 5,10 methyleneTHF to 5THF  provides a methyl group to convert homocysteine to methionine. This important part of the methylation cycle is brought about by the enzyme MTHFR.

The activity of MTHFR is a very important rate limiting step in conversion of homocysteine to methionine. Vitamin B12 plays a very important role in these chemical processes. 

Interestingly, SAM actually inhibits the action of MTHFR. This important biochemical property of SAM was discovered by Jencks and Mathews in 1987.[2]. Therefore, supplementation with SAM is contra-indicated because it would have the potential to contribute to the build-up of homocysteine because it inhibits the activity of MTHFR. Supplementation with 5THF would be considered to be of greater help with conversion of homocysteine rather than SAM.

Significance of Homocysteine.

As indicated above, estimation of the level of homocysteine in the blood is helpful in the determination of the level of disease susceptibility. Homocysteine is measured by a routine blood test. Normal levels of homocysteine are in the order of less than 13 μmol/L. A level between 13 and 60 μmol/L is considered moderately elevated, and a value greater than 60 to 100 μmol/L is severely elevated.

Another test, the methionine-load test measures homocysteine levels in the blood before and after the intake of 100 mg/kg of methionine. This test is used to diagnose abnormal homocysteine metabolism. Vitamin B6 supplementation may be useful in those with abnormal homocysteine metabolism.

How to Deal with Defective MTHFR Genes

The main approach is to lower homocysteine as much as possible. Homocysteine levels may be reduced by increasing intake of folate and vitamins B6 and B12. This can be done by increasing intake of foods rich in these substances such as greens, nuts and cereals etc. Supplementation is also recommended. Folate from foods is superior to that synthesized in the laboratory.

Other Considerations

• SAM or Adomet supplementation is often suggested as a way of increasing a person’s methylating capacity. This option is not recommended because, as indicated above,[2] Jencks and Mathews in 1987 have shown that SAM reduces the activity of MTHFR.
• Methionine supplementation is not necessarily recommended because it is now known that reduced methionine intake is associated with increased lifespan, see Ref. 3.[3]
• Activation of the MTHFR gene. To re-affirm, it is not recommended that boosting of the activity of the MTHFR gene is attempted unless it is known that the person has inherited two non-mutant forms of the MTHFR gene.

Further Infomation

For further discussions please contact me by email at peterhkay@gmail.com

References.

1. www.ncbi.nlm.nih.gov/books/NBK6561/
2. www.jbc.org/content/262/6/2485.short
3. www.benbest.com/calories/Meth.html