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S2E28: COMT and MTHFR.

To kick off our series on other polymorphisms, I’m starting with another heavy-hitter that is deeply entwined with MTHFR.  This polymorphism is also in a gene that codes for an enzyme by the name of catechol-O-methyltransferase.

I’m hoping that right off the bat, you noticed the word “methy”l in there as part of the enzyme name. That is important in terms of how it ties in with MTHFR. So let’s break this name down.

Catecholamine = the group of compounds that this enzyme acts on. In fact, it metabolizes these substances as part of the break-down process.” Catecholamines are a very important group of hormones, many of which do double duty as neurotransmitters, that have a similar structure and are all highly biologically active.  They include dopamine, norepinephrine, epinephrine, and a group of estrogenic compounds called catecholestrogens.

It doesn’t take a vast wealth of biomedical knowledge to know that an enzyme that affects stress hormones, neurotransmitters, and estrogens is going to matter. Really matter.

Catechols are also found in foods, drinks, and supplements and the COMT gene can change the way we respond to those as well. Coffee, beer, buckwheat, green and black tea, chocolate, peppermint, parsley, thyme and many other fruits, vegetables, and herbs all contain catechols. In terms of supplements, EGCG (from green tea), green coffee-bean extract, rutin, and quercetin.

A quick note on the supplements – they generally act as COMT inhibitors, which can be a good thing if your COMT is overly fast, but not so good if you have a slow COMT.

As for the next part of the name, “O-methyltransferase” – this refers to the specific action taken at this particular step in the breakdown process. We’re transfering a methyl group to a particular location (designated “O”). And by methyl group, I mean from a SAMe, made by your MTHFR.  So if your MTHFR is limping along, then COMT is by  nature compromised because there isn’t enough SAMe or enough methyl donors to go around.  So these two enzymes are highly tied together. This is also a big part of why MTHFR folks often have issues with estrogens.

COMT and MTHFR, COMT fast, COMT slow

There is one other breakdown pathway for these neurotransmitters, which is via the MAO series of enzymes, all of which can also have polymorphisms, so there is a lot of symptom overlap between COMT and MAO mutations.

It may sound like COMT isn’t important because it isn’t about formation of these products, it’s about breakdown, but in reality, breakdown is just as important.  Overly efficient breakdowns means that the substance is cleared too quickly and you don’t get all the benefit, while breakdown that is too slow means the substance hangs around for too long doing damage. 

There are several COMT mutations and they have additive effects to make the overall activity of the enzyme either faster or slower than the wild type genetics. The most studied so far is COMT Val158Met.

COMT Val158Met (or rs4680, or G158A because genetics can’t keep its names straight).

This is a really interesting polymorphism because it can take a person either faster or slower, depending on it’s presentation. In the next two weeks we’ll dive into the idea of faster and slower and what that means for the person experiencing it.

Met/Met = estimated to be 40% slower than “wild type”

Val/Met = intermediate activity

Val/Val = faster than average COMT activity

There are other COMT polymorphisms as well, but I do want to caution you from trying to figure out your fast/slow status from a genetic report. The symptoms and signs of fast and slow COMT are very clear and easy to see and they’re far more accurate than us doing theoretical math on gene SNPs. Remember that genes can actually have a polymorphism, but they can also act like they have a polymorphism because of nutrition, lifestyle, and epigenetic factors so the most important factor in figuring out whether you’re fast or slow is your symptoms and personality.

COMT and MTHFR

There is a really strong link between your MTHFR status (and more importantly, how well you’re methylating) and your COMT activity. Remember the O-methyltransferase part? Well, we can only transfer methyl groups if we have methyl groups and in order to have a healthy supply, methylation needs to be happening well.

This might sound simple, but it essentially means that healthy COMT function depends entirely on healthy methylation, so without doing your methylation background you can work on COMT until you’re blue in the face and it isn’t going to fix things.

This also means that if you’re pushing methylation too hard – say you’re taking great big doses of methyl folate or SAMe and (somehow) tolerating it well but not really needing it? That has the potential to push your COMT into too-fast territory.

The supplements that can push COMT too fast are:

  • methyl-cobalamin (this is one that I see people take far too much of really frequently).
  • betaine / TMG
  • 5-LMTHF or methyl folate
  • SAMe

You’ll notice these are all the drivers of methylation and your big methyl donors.

COMT, also needs a cofactor and that is magnesium. Just like MTHFR needs B2, or riboflavin, to do anything at all, COMT needs magnesium. Fast or slow, this is a great addition to your routine, especially at bedtime because magnesium is physically and mentally relaxing.

Thanks so much for listening and next week we’ll dive into the COMT slow personality type and picture and also what you can do if you have COMT slow. Thanks so much for listening, and if you might be interested in a 6 Weeks to Amazing MTHFR course and workbook, then you’d better get into Genetic Rockstars or sign up for the mailing list at tohealthwiththat.com right now.

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