What is MTHFR?
MTHFR stands for methylenetetrahydrofolate reductase. It is a gene that encodes an enzyme by the same name. This enzyme is involved in the methylation pathway. Methylation is a biological chemical process that takes place billions of times over in your body each day. A methyl group consisting of one carbon atom and three hydrogen atoms is added to a molecule to carry out many different biological processes in the body. With these donors,the body can do things like make hormones, neurotransmitters, DNA repair, switch genes on and off and provide energy.
There are many cofactors and methyl donors needed for this process to function correctly. Methyl donors are SAMe, Betaine, Methionine and Choline, while Cofactors include B9, B12, B6, B2, magnesium, zinc, molybedum and selenium.
How Methylcobalamin is made
Vitamin B12 is found in foods such as meat, fish, and dairy. It naturally occurs in various forms like hydroxocobalamin, methylcobalamin, or adenosylcobalamin, all of which are bound to proteins. The digestive process begins in the stomach, where hydrochloric acid and the enzyme pepsin work to release B12 from these proteins. Once free, vitamin B12 binds to a protective protein called haptocorrin, which protects it from the acidic environment of the stomach.
Pancreatic enzymes in the small intestine break apart the B12-haptocorrin complex, freeing B12 again. It then binds to intrinsic factor (IF), a protein that is essential for B12 absorption. The IF-B12 complex then travels down to the ileum, the final section of the small intestine, where it is absorbed into the bloodstream for the body to use. This process ensures that vitamin B12 is delivered to cells to support critical functions.
After absorption, B12 binds to transcobalamin II (TCII) which delivers B12 to tissues and cells. The gene TCN2 plays a crucial role in the transport and delivery of vitamin B12 in the body. These genes encode specific proteins, transcobalamins, which bind vitamin B12 and help its transport to cells where it is needed for metabolic processes. Genetic mutations in the TCN1 and TCN2 genes or deficiencies in transcobalamin can lead to functional B12 deficiency, even if dietary B12 intake is sufficient.
The FUT2 gene (fucosyltransferase 2) influences the gut environment, which is really important for the early stages of vitamin B12 absorption. FUT2 determines secretor status, referring to whether an individual produces fucose in the gut lining. Fucose act as nutrient and binding sites for beneficial gut bacteria, such as Bifidobacteria, which help maintain the integrity of the gastrointestinal lining. A healthy gut environment supports the production and function of intrinsic factor, that is secreted by stomach cells that binds to B12 and aids in its absorption in the small intestine. Non-secretors often experience negative changes in their gut microbiota, which may indirectly impair the efficiency of intrinsic factor and reduce B12 absorption which can lead to anemia.
Once inside the cell, cobalamin is released from TCII and transported to the mitochondria or cytoplasm. In the mitochondria, cobalamin is converted into adenosylcobalamin for energy metabolism.
In the cytoplasm, cobalamin is converted into methylcobalamin by the enzyme methionine synthase for its role in the methionine cycle. This reaction requires 5-methyltetrahydrofolate (5-MTHF), the active form of folate, which donates the methyl group.
Methylcobalamin serves as a cofactor for methionine synthase, (MTR) helping the conversion of homocysteine into methionine, a key step in the methylation cycle. After donating the methyl group, methylcobalamin is recycled back into cobalamin, ready to be converted into its active forms again.
B12 status is dependent on adequate levels of methylfolate which acts as a methyl donor for B12, as well as B2 and B6. Genetic variants in the MTR gene can affect methionine synthase activity. FUT2 and TCN2 can also affect B12 getting into the cells. A healthy digestive system is necessary for proper absorption and conversion of B12.
How Methylfolate is made
Folate is found in foods such as leafy greens, your body converts them into tetrahydrofolate . The enzyme MTHFD1 (which needs choline) helps convert THF into 5,10-methylenetetrahydrofolate, a form of folate that’s ready for further processing. The next step involves the enzyme MTHFR , which reduces 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate or methylfolate, the active form that is used in the methylation cycle. When you have mutation in MTHFR, depending on what allele you have, it can reduce this conversion by anything from 20-70%.
Methylfolate plays a key role in converting homocysteine, an amino acid, into methionine, a process vital for producing proteins and other important molecules. This conversion is needs the enzyme methionine synthase, (MTR) which requires vitamin B12 as a cofactor. Without B12, methylfolate cannot donate its methyl group to homocysteine, causing a buildup of homocysteine in the blood.
This is why B12 is essential for the proper functioning of the methylfolate pathway.Without B12, folate can’t be used. This is known as the methyl-folate trap. Other vitamins and minerals, like vitamin B2, vitamin B6, and magnesium, are needed to support these enzymes and help the entire process work efficiently.
Methycobalamin and Methylfolate supplements
These two supplements are potent due to the fact that they are bioavailable. This means the steps to convert them from their original state (dietary sources) had already been done for you. It cuts out many enzymatic steps. This is especially useful if you have genetic mutations that can hinder this conversion process. However, since these supplements are so bioavailable, it can speed up the methylation pathway, sometimes too quickly.
We already have seen that B12 and B9 are a co-dependant team. One needs the other. We have also seen that in order for B12 and B9 to work correctly, they need cofactors and methyl donors as well as a healthy gut microbiome. This is where things can go wrong…
Learning you have MTHFR
You get a DNA test and find out you have the MTHFR gene and after reading about it, you decide the best thing to do is to take either B12 or B9. This can be a mistake. Remember I said that B12 needs b9 and B9 needs B12? Well, taking just one of these highly bioavailable supplements will mean you already are upsetting the delicate balance that requires BOTH of these nutrients. It also depends on what alleles you have and as well as other factors.
To find out how COMT, MAO-A are involved, overmethylation and other factors that are important to consider when deciding to supplement and what form (methylated versus non-methylated) please sign up for my Genetic Wellness lifetime membership, where you can access a wealth of information by paying a once-off fee. New articles are constantly being added.
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