Where to find basic explanation of methylation, MTHFR etc.?

I gather that there's a lot of controversy about this whole area and I'd like to mug up on it so I can understand it. I expect a few other folks would, too.

I know bugger all about genetics and I don't have a bioscience background. I don't want to spend 20 hours on Coursera, though! I just want to read a few articles that will get me up to speed, supplemented if necessary by looking things up on Wikipedia (such as what a chromosome is, etc.).

Any recommendations?

@Valentijn? Not sure who else to tag...

 

PR had good Rich van Konyenburg(?) info re methylation (from a glutathione perpective)

 

@alicec ?

 

Methylation is about the transfer of single carbon units (methyl groups) which are used in a wide variety of biosynthetic processes in the body.

At the heart of 1C transfer is the folate cycle which mediates three biosynthetic pathways, de novo synthesis of purines, thymidylate synthesis and the remethylation of homocysteine to form methionine (a B12-dependant reaction).

Here is an illustration of these pathways which is derived from this paper.

Methionine in turn is a precursor for the synthesis of S-adenosylmethionine (AdoMet or SAM), a cofactor and methyl group donor for numerous methylation reactions, including the methylation of cytosine bases in DNA, histones, RNA, neurotransmitters, and other small molecules, phospholipids, and other proteins.

S-adenosylmethionine–dependent methylation reactions serve to regulate fundamental biological processes, including gene transcription, mRNA translation, cell signaling, protein localization, and the degradation of small molecules.

The primary source of one-carbons for cytoplasmic one-carbon metabolism comes from formate that is derived from mitochondrial one-carbon metabolism and the ultimate source of formate is the amino acid serine.

Here, here and here are university websites which illustrate the pathways in different ways. Sometimes people find different approaches more understandable.

Here is a paper which quantitates the relative importance of the different pathways, concluding that

Here is just one old review which canvasses some of the ways these pathways are thought to be relevant to various health conditions. It is old but it does set things out clearly.

How does all this relate to ME/CFS?

We don't really know, though people have various theories. Certainly many people in another place have reported benefit from folate/B12 supplements, though many don't.

The recent work of Naviaux might provide some clues about this. He found widespread metabolic derangement in ME/CFS patients, all of which were either directly regulated by redox or the availability of NADPH.

1C metabolism is directly related to this since transulfuration produces cysteine, the rate-limiting step in synthesis of the ultimate redox controller glutathione, while one of the folate cycle enzymes (MTHFD2L) is an important source of NADPH.

This reference to MTHFD2L might be confusing since it is not shown in the diagrams I linked.

To make a complicated picture even more complicated, you need to realise that the folate cycle occurs also in mitochondria and uses slightly different enzymes from the illustration I linked for cytoplasmic and nuclear compartments.

MTHFD2L operates in the mitochondrion only.

This figure from this paper shows the cytoplasmic and mitochondrial pathways in parallel.

In the cytoplasm, MTHFD1 is tri-functional. Reactions 1-3 in the figure are all carried out by a single enzyme with 3 different capabilities incorporated into a single protein.

In the mitochondrion, however, the three functions have been split. MTHFD1L carries out one function (reaction 1m) while MTHFD2L carries out the other two (reaction 2m and 3m). There is another enzyme, MTHFD2, which has a similar function to MTHFD2L, but it is found in very restricted circumstances. MTHFD2L is the enzyme which normally performs this function in adult cells.

So what about SNPs, including the one that seems to have generated an enormous amount of internet chatter - the C677T variant of MTHFR.

Well there are a number of common SNPs which do affect reactions in the cycles discussed above, but the effects have been greatly exaggerated. Furthermore the SNPs are very common - many millions of people live with them without apparent difficulty.

In general the SNPs slow certain enzymes but it appears that healthy people eating well can cope with this. They can be problematic under conditions of increased need, eg pregnancy. Certain disease states may also increase demand though there is little research on this.

With ME/CFS where there appears to be widespread metabolic derangement, I think that if one has SNPs known to slow any enzyme, then it is wise to consider supplementing either the cofactor for the enzyme or the end product of the reaction which is slowed - but that is just my opinion. The benefits or otherwise of such supplements would need to be assessed empirically.

@Valentijn started a number of threads in another place on SNPs affecting various enzymes in methylation pathways.

These include MTHFR which produces 5 methylfolate which is used in the methylation of homocysteine to produce methionine; MTR and MTRR which catalyse this reaction (all of which have common and uncommon SNPs which do slow the enzyme), along with other enzymes for which claims are made but for which there is little or no evidence - eg BHMT used in another pathway to methionine production, and CBS which starts the transsulfuration pathway.

If there are particular enzymes or SNPs you would like to know more about just ask.

 

Thanks, @alicec! I'm going to print that off and study it.

 

Thanks very much @alicec . The perfect reminder to me that if I'm going to understand this I need to do more Coursera courses on cellular biochemistry! I've done a couple of introductory ones, but I need much more depth to follow all this.

I think I'll start a thread where we can share information on useful courses and books.

 

I've not looked at that page before. It does repeat a number of Yasko's errors.

 

Thank you so much @alicec. A couple of hours ago I was despairing of my addled ME brain ever grasping this, but your straightforward explanation has helped me enormously.

I've tried to wade through Ben Lynch's information, but there's just too much there, and how much is hype?

How do we decide whether it's worth getting tested? Should all of us horribly ill people do it, just in case we find something useful?

 

Hoping that someone may have a better memory than me. (Yes I do know where I am!)

Does anyone recall a recent post, perhaps in the last 2 weeks, which was in relation to B12 and methylation and was in reference to work by Davies and/or Naviaux. It'll be unpublished.

 

Thanks @alicec .
This will be my homework this week. A nutritional therapist helped with gut issues after H Pylori and suggested DNA analysis. I have report but not dataset, but there would appear to be significant methylation issues .
Both MTHFR 677 and 1298 and MTR and MTRR SNPs , and complete absence (?) of GSTM1 .
Also inflammation IL6R, TNF alpha and fat and glucose issues....

How usual is the absence of genes?

 

This varies greatly - it depends on the gene. In the case of GSTM1, the deletion mutant is very common, the frequency ranging from about 0.3 to 0.5.

GSTM1 is one of 7 versions of cytoplasmic GST, so other isotypes can step in if the M1 type is absent. There has been some suggestion that the GSTM1 null variant is associated with increased cancer risk, but other studies have not verified this, so if there is a risk it would be very small.

 

Thanks @alicec
This is a whole different ballgame for me!