Hole in the Bucket

Toward Understanding the SAM and
Folic Acid Cycles


A Hole in the Bucket

by Ginger Houston-Ludlam

There have been many questions on all the alphabet soup of the SAM and Folic Acid cycles as they relate to Down syndrome. Let me see if I can try to make some sense of it all, clinging as close to English as I can. If this starts to sound like Greek (or more correctly, Latin) then please accept my apologies.

What Is All This Stuff? MTHFR Mutation High Homocysteine TMG

What Is SAM, B12, Folic Acid and MTHFR?

The first question I’ll address is what folate/folic acid, MTHFR, SAM and B12 and all this other stuff is that you’ve never heard of. And what is an MTHFR anyway? And what does this have to do with Down Syndrome?

There are two reasons that we are very concerned with all this stuff. First, the folate/SAM cycles are messed up in Down syndrome due to the triplication of two particular genes. Secondly, many of the mothers on the Internet Down syndrome lists participated in a research study and learned that they had a mutation in the gene for MTHFR. MTHFR is an enzyme that is part of the folic acid cycle. This mutation has health implications for the mothers as well. Therefore, the kids and the moms are messed up in terms of folic acid, although by different mechanisms.

Before I discuss those mutations, let me back up just a little bit, and talk a little bit about biochemical cycles, and then what the folate and SAM cycles are, and why they are important.

Biochemical Cycles

Biochemical cycleMany chemicals in the body operate in “cycles.” In other words, if you draw what happens to them, it goes in a circle with a number of steps (see Figure 1). Chemical A+ becomes Chemical A- which becomes chemical B- which becomes chemical B+ and then back to A+. At each step, the chemical interacts with an enzyme (usually with a very long name, and ending in the suffix “ase”) which does the actual conversion from one chemical to another. There will be one enzyme that comes along and converts the + to a – in the above example. The – form will then have another enzyme convert it from A to B or whatever. So, in my A/B example, there are four steps in the cycle, with four enzymes to convert it, one at each step. Then, when we throw the 18 syllable words at you (actually, MTHFR has only 12 J) it will make sense.

Another general principle of cycles is that at each step, the base chemical in the cycle (in this case, folic acid) is either gaining a piece or losing a piece. That piece can be something as simple as a single electron. Oxidation, which you will hear talked about a lot, is actually the loss of a single electron, and reduction, the polar opposite, is the gain of a single electron. Or the piece lost or gained can be a huge chunk of amino acids when a protein is cleaved (like bad old Amyloid Beta; it’s the one that makes plaques in Alzheimer’s disease and the precursor protein is triplicated in Down Syndrome.) For those of you who have read my bus route analogy, each of the four chemicals or “bus stops” is a place where something gets on or off the bus (base chemical).

Methyl groupIn the SAM and Folic Acid cycles, we will mostly be talking about the “methyl group” getting on or off. All a “methyl group” is, by the way, is three hydrogens bonded to a single carbon (Figure 2). When a chemical receives a methyl group, we say that the chemical is methylated. Methylation is the process of putting methyl groups on a chemical. We will see in a moment that when a methyl group jumps from folic acid to homocysteine, homocysteine is methylated.
In most cases, these chemical reactions involve two chemicals. Usually, an enzyme will grab a chunk off one chemical and give it to another. Most of the time, we only focus on the stuff in the cycles themselves, but usually there’s a poor little water molecule whose hydrogens get ripped off its little body by the enzyme and given to the chemical on the bus route. The fact that oxygen (O2) is created when this happens twice is often not discussed. In some cases (like what happens to homocysteine) it is important to understand that one chemical loses what the other chemical gains in the reaction, and that these processes are tied together chemically. That very reaction is where the folic acid and SAM cycles come together.

When these cycles are operating normally, each chemical moves through all four (or however many) steps continuously. Of course, there are many, many copies of each of these chemicals being converted by many copies of enzymes. So, once you understand the conversions, you need to start thinking of these not as single chemicals, but buckets full of each and pumps (the enzymes) to move the chemical from one bucket to the next.

Problems in Biochemical Cycles

Problems in these cycles generally are of two types, both of which play into the problems with the MTHFR enzyme and Down Syndrome in general. One type of problem is that something comes along and pokes a hole in one of the buckets. So, over time, there isn’t enough in one of the buckets to pump into the next one. The cycle then runs out of that chemical unless someone comes along and pours a whole bunch of the chemical into the holey bucket. This happens when you take a supplement, or eat a meal full of that chemical. The thing that operates like a hole-puncher in Down Syndrome is the triplicated Cystathionine-Beta Synthase gene, also referred to as CBS. It messes up the cycle by stealing homocysteine out of the SAM cycle. We will talk about that more later. The other type of glitch happens with the enzyme, the mechanism that pumps from one bucket to the other. If the enzyme won’t pump, then what you find is that one bucket gets filled to overflowing, but all the buckets in the cycle after that one become empty. The chemical gets “trapped” at the bucket with the bum pump. When the MTHFR enzyme is mutated (as it is in many moms of kids with Down Syndrome) and doesn’t work properly, one form of the folate molecule is trapped in its bucket, as we will now discuss.

The Folic Acid Cycle

Folate CycleThis cycle has three stops on it. At stop one (chosen arbitrarily), THF steals a “methylene” from Serine to become MethyleneTHF. THF is short for TetraHydraFolate for anybody who’s a masochist like me and wants all the details. Also, there’s a bit more than just stealing one thing going on here, so for those of you reading this who are actually chemists, forgive me my sin of oversimplification here. Stop two: Methylene-THF is then converted to Methyl-THF by the enzyme (…drumroll, please…) MTHFR, also known as methylenetetrahydrafolatereductase, (Figure 3). Stop three: Methyl-THF is converted back to THF by the enzyme Methionine Synthase plus vitamin B12. B12 moves the methyl group from Methyl-THF and gives it to Homocysteine which then becomes methionine. Clear as mud?

The folic acid cycle (also called folate cycle) and SAM cycle connect at B12, (Figure 4). Here is where all the rubber meets the road. Any deficiency anywhere in the folic acid or SAM cycles rears it’s ugly head right here. Folic acid deficient? The homocysteine bucket fills up (you can measure high homocysteine in the blood) and everything comes to a screeching halt. B12 deficient? Both homocysteine and Methyl-THF buckets fill up and everything comes to a screeching halt. Homocysteine bucket has a hole in it? The Methyl-THF bucket fills up and everything comes to a screeching halt. MTHFR is mutated? The Methylene-THF bucket fills up and everything comes to a screeching halt. In Down Syndrome the homocysteine bucket has a hole in it because the CBS gene is triplicated so CBS steals more than its fair share of homocysteine.
Folate and SAM cycle
“OK, so what?” you say. “So we have a few overflowing buckets.” The bad news is that all of the stuff that is supposed to be happening on the other side of that reaction in the cycles is not happening because the buckets supplying those reactions are empty. The big news for the folic acid cycle is that the raw materials to make DNA are not being produced. (This happens at a slightly different path from methylene-THF that we haven’t talked about yet, and I don’t want to because this is muddy enough already.) The big news for the SAM cycle is that all of the chemicals in the body that are supposed to be methylated by SAM are not being methylated. Methylation turns genes on and off. Many chemical reactions in the body require methyl groups to proceed. SAM is the official methyl donor for the entire body. If anybody needs a methyl group, they get it from SAM. (Sam, Sam the methyl man.) A lot of things need methyl groups.

Just for completeness, and which might be of help to people who have participated in Jill James’ study (since all of these names will be on your report) the four “stops” on the SAM cycle are Homocysteine, Methionine, S-adenosyl Methionine (SAM) and S-adenosyl Homocysteine (SAH). Otherwise, those names don’t really matter at all.

The MTHFR Mutation

So you ask, “How do I know if I have a bad MTHFR if I missed Jill’s study? (And who is this Jill person anyway?)”

Jill James is a Ph.D. biochemist who does research in folic acid for the FDA. She is a world class scientist. Her background, actually, is in cancer research. She is also one of the scientists on the Scientific Advisory Committee that controls the formula for NuTriVene. Most of us originally came into direct contact with her when she recruited subjects for the “mom” study on the DS-Nutrition list about two years ago. This is when moms learned for sure that they have one (or a couple of) MTHFR mutation(s). That study is complete, and the results were published in October, 1999 in the American Journal of Clinical Nutrition. The study showed that mothers of children with Down Syndrome disproportionately had MTHFR mutations, and usually had the corresponding high homocysteine and other indicators in their blood. That study is over and, with a very few special exceptions, Dr. Jill is not taking mom blood anymore.

The alternative to having your MTHFR genes checked is to get your doctor to run a homocysteine test on you. If your homocysteine is high, then you have risks of birth defects and placental problems in future pregnancies and you also have a risk, yourself, of heart disease. According to some papers I am reading, elevated homocysteine is every bit as big a cardiac risk as elevated cholesterol. Because you have a child with Down Syndrome, you also have a corresponding increased risk for heart disease, and your doctor should treat you accordingly. The MTHFR mutation itself is not dangerous. The metabolic side effects are dangerous, yet they can be treated with a particular group of vitamin supplements.

If You Have High Homocysteine Levels

The good news is that the effects of the MTHFR mutation are relatively easy to fix. What you need to be taking is extra folic acid (shoot for 800 mcg per day), TMG (500 mg to 1 gram per day), and methyl B12 (at 1 mg per day). For someone without Down Syndrome, you can also add B6. You do not want to add B6 in Down Syndrome, because it is part of the process that CBS uses to drain homocysteine from the SAM cycle. You could make matters worse by using B6 in excess or out of proportion of what’s already in the NuTriVene. You really want to be taking all of these things if you have the MTHFR mutation or if you suspect that you do because of high homocysteine. They all nudge things along at various places. The problem with premixed formulas for lowering homocysteine that are available at the health food store is that they are using a sub-optimal form of B12. Methyl-B12 is the active form, and will most dramatically affect the imbalances. However, it must be taken sublingually (under the tongue) so it can’t be wrapped up in a handy-dandy, easy-to-swallow pill.

What is TMG?

TMG is Tri-methyl Glycine, or a form of Betaine. That means it is a Glycine molecule with three methyl groups attached. It fits into this whole picture as an alternative path to convert homocysteine to methionine (alternative to B12 plus Methionine Synthase). There is another enzyme called betaine-homocysteine methyltransferase (BHMT) which specifically snags one methyl group off of TMG and hands it to homocysteine to convert it to methionine. Guess what TMG becomes when BHMT steals a methyl group? Dimethyl Glycine, or DMG. The third methyl group is the one that helps with this whole SAM cycle. At that point, the DMG feeds into the folic acid cycle and feeds the immune system, helps to increase serotonin, and all the other benefits of having a properly functioning folate cycle. TMG and M-B12 are both available from the Life Extension Foundation and from International Nutrition.


This article was originally written as a post on the DS-Nutrition email list in November, 1999.