Part 2: The Four Pathways of Homocysteine – Are One Or More of Your Pathways Blocked?

Part 2: The Four Pathways of Homocysteine – Are One Or More of Your Pathways Blocked?

In my last post on homocysteine I discussed homocysteine as an extremely important lab marker that is rarely run. I discussed the optimal range being between 6-8 (some would argue 4-8). I discussed how levels above and below the optimal range can create health challenges by hindering methylation.

In this post I want to discuss one of the four pathways of homocysteine in the body. In Part 3 and Part 4 I will describe the other pathways.

An elevated homocysteine level is one of the more common findings I see in people with chronic healthcare problems. Elevated homocysteine has been shown to be a contributing factor in vessel damage, high blood pressure, cardiovascular disease, stroke, migraines, Alzheimer’s disease, dementia, macular degeneration, and cancer.

So, step one is to make sure you have your homocysteine levels evaluated. The next step is to determine if your level is in the optimal range. And the third step is to determine if it is not in the normal range, why and how to address getting it within range.

Homocysteine is critical for health. We need it. It is part of so many vital processes in the body. But if it is high or low, we want to know why. If homocysteine is elevated we can than assume that there is a block in 3 of the 4 possible directions homocysteine can travel once it is formed. If there is a block in one or more of the pathways, homocysteine can become elevated and create damage.



There are four possible fates of homocysteine once it is formed.

  1. It can be recycled to methionine via MTR
  2. It can be recycled via BHMT in the liver and kidneys
  3. It can be cleared through the Transsulfuration pathway
  4. It can be reversed back to S-Adenosylhomocysteine (SAH) from which it came.

Problems in the first three pathways will have a tendency to increase homocysteine levels. If there are elevations of homocysteine, it can preferentially drive backwards to SAH without much resistance. This will increase levels of SAH, potentially inhibiting methylation reactions in the body. The discussion of SAH will be left for another post.

The first pathway and the primary fate of homocysteine is to recycle homocysteine to methionine. This reaction requires methylfolate, methylcobalamin, and zinc. Along with these three components, three enzymes are critical to allow this pathway to proceed.

The first of the three enzymes is Methyltetrahydrofolate Reductase (MTHFR). This enzyme gets a lot of press. The enzyme is responsible for converting dietary, supplemental, and recycled forms of folate into 5-Methyltetrahydrofolate (5MTHF) which is required for recycling of homocysteine through the primary pathway. Anything that impedes this enzymes function will reduce the amount of 5MTHF produced and lead to a potential increase in homocysteine.

There are a number of factors that can affect the amount of folate getting to MTHFR for conversion to 5MTHF: a low folate diet, high intake of folic acid from supplements and processed foods, medications that block folate absorption or utilization, defects in genes that code for enzymes required for the steps preceding the MTHFR enzyme, and any factors causing slowing of the enzymes.

If we can increase our intake of raw leafy greens, other folate rich vegetables and foods, and reduce our intake of synthetic folic acid, we can generally optimize folates getting to the MTHFR enzyme for conversion.

Unfortunately the MTHFR enzyme can be one of the major choke points inhibiting homocysteine recycling. There are multiple factors that can inhibit MTHFR function: SNPs, reduced levels B2 and B3, reduced levels of activated forms of these vitamins, low levels of free T4 which is required to convert B2 into it’s activated form FAD, and high levels of SAM (usually from supplementation).

The second enzyme is Methionine Synthase (MTR). This enzyme is used to drive the conversion of homocysteine to methionine with the support of 5MTHF, methylcobalamin, and zinc. Deficiencies of any of the cofactors will reduce the recycling of homocysteine. Elevated levels of nitric oxide, lead, mercury, hydrogen peroxide, aldehyde, and THF alpha can inhibit this reaction as well. Anything that increases oxidative stress on the body will reduce the MTR enzyme reaction so that more homocysteine can be shunted down the transsulfuration pathway to produce more glutathione, the major antioxidant in the body.

There are some SNPs that can affect the function of this enzyme. The most discussed SNP is MTR A2756G. This variant tends to increase the speed of the reaction. The MTR enzyme aids in the conversion of homocysteine to methionine by transferring the methyl group from 5MTHF to homocysteine creating methionine and tetrahydrofolate (THF).

Once the MTR reaction occurs, the methionine can be converted into s-adenosylmethionine (SAM), the major methyl donor in the body. The THF is than recycled back into the folate cycle and the cobalamin can be recycled back into methylcobalamin to be used to recycle another homocysteine molecule.

The third enzyme in the pathway is Methionine Synthase Reductase (MTRR). MTRR along with it’s cofactors SAM, FAD, and NAD recycle cobalamin back into methylcobalamin. Any reduced activity of this enzyme will limit methylcobalamin production and the ability to recycle homocysteine. Not only will we see homocysteine levels rise, but this is also the cause of what has been called “methyl trapping”.  “Methyl Trapping” refers to the methyl group on MTHF not being able to be transferred to homocysteine essentially being trapped and not usable.

An interesting point here is that if someone just tested serum folate, folic acid, and B12 levels, the patient’s levels may show normal to elevated levels. The doctor not knowledgeable in methylation might assume the person has optimal methylation capacity or is over consuming folate or B12.

That’s the first pathway for homocysteine recycling. I’ll discuss the other pathways in Part 3 and Part 4 as well as how to think through what we see on labs and how to address homocysteine levels.

Dr. Eric Balcavage

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  1. What specialist should I ask for these blood tests?
    Would my endocrinologist be appropriate?

    • Andrea,

      Any doctor can run a homocysteine test. Not every doctor knows how to interpret what the value/test result means and how to correct.

      I think you would be better off with a functional medicine practitioner like myself. If your doctors haven’t run it at this point it is a good indicator they don’t understand it’s importance. To be fair, there is no drug to give for high homocysteine so it is rarely run. Ask your primary to run it for you. If primary won’t than ask endocrinologist.

      Just out of curiosity why do you have an Endocrinologist?

      If you have immune system problems, thyroid, diabetes, or hormone problems this test becomes even more important.

  2. Hello Doc,

    I hope you can help me with a running debate I am having with a fellow practitioner. He insists that is no harm to increasing methylation by increasing the level of folic acid as opposed to use MTHF and running the risk of overmethylating the patient.I realize that all associated pathways need to be supported as well but could you please point me to some hard data showing that folic acid can have a detrimental or suppressive effect on methylation?? this would allow me to put our running battle to an end!

    Jerry Morrison ND



  1. Part 3: (Homocysteine) The BHMT Pathway | The Methylation Doctor - […] I’m back with part 3 of our Homocysteine blog series.  In part 2, I covered the primary recycling pathway…
  2. Part 5: Homocysteine and the Reverse Reaction Back to SAH | The Methylation Doctor - […] Part 2: The 4 Pathways of Homocysteine: Are One Or More of Your Pathways Blocked? […]

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