SNPs for Dihydrofolate Reductase (DHFR)

[Bluebell]

LaurieL : Mine are similar to yours. But several of the DHFR SNPs have exactly the same prevalence in the same sample groups, so are probably inherited as a chunk. One such cluster is red, and the other is green. Our differences from the Richvank genotype are orange.

RSID........ALLELE.....RICH...LAURIEL....VAL...
rs7387......A or T...TT (-/-) AT (+/-) AT (+/-)
rs1643659...C or T...TT (-/-) CT (+/-) CT (+/-)
rs1677693...G or T...GG (-/-) GT (+/-) GT (+/-)
rs1643649...C or T...TT (-/-) CT (+/-) CT (+/-)
rs11951910..C or T...TT (-/-) CT (+/-) TT (-/-)
rs865646....G or T...GG (-/-) GT (+/-) GT (+/-)
rs13161245..A or G...AA (-/-) AC (+/-) ?? (?/?)
rs10072026..C or T...TT (-/-) TT (-/-) TT (-/-)
rs11490741..C or T...CC (-/-) CC (-/-) CC (-/-)
rs863215....C or T...CC (-/-) CT (+/-) CT (+/-)
rs1478834...A or C...CC (-/-) AC (+/-) AC (+/-)
rs1650697...A or G...AA (-/-) AG (+/-) AG (+/-)

So we have the same "red" and "green" groups, which are different from Richvank's, as well as rs7387 and rs1650697. Our only difference from each other is that I have the Richvank version of rs11951910.

Valentijn, I believe that you misunderstood what NanDixon said about Richvank's results.

You have indicated in your table here that Rich's result for rs1650697 was AA. However, that is what NanDixon said HER result was. She stated that rs1650697 was the only one where she differed from Rich's.

She also stated that Rich's results were all homozygous and all "-/-", so that probably means that Rich's result on rs1650697 was GG, the only other possibility if NanDixon's "+/+" AA homozygous result was different from his.

In her original post, she wrote: "....his results appear to be completely normal (homozygous -/- throughout). Mine are identical to his with only one exception: the SNP rs1650697 (aka C35T or G-437A) that overlaps with a coding region for the gene MSH3 is homozygous (+/+) for the variant alleles (AA)....
Below are my results for people to compare to theirs.... rs1650697 AA (+/+)."

I have not tried to search for the thread where Rich reported his original 23andme results, but that would be the best way to make sure, of course.

 

[Bluebell]

Mine are the same as Rich except for a CT for rs10072026, which is different from all of you

Sea, I also have a CT at rs10072026, just like you --
and otherwise, like you, I match Rich's results
(if NanDixon was saying that Rich's rs1650697 was GG -- see the preceding post I made about that rs number -- which is also my result on that one, GG).

As far as I can tell on DBsnp, the CT at rs10072026 was in about 20% of a European sample, but was not very common in other samples of ethnic groups that are listed there.

 

[Bluebell]

nandixon said: ↑

To assist in producing more BH4 from BH2 (via DHFR) you would want to avoid the known inhibitors of DHFR, including folic acid and green tea (especially green tea extracts, eg, EGCG).​

Do you think the other component of green tea, L-theanine, can inhibit DHFR? I ask because someone I know who has problems with methylation cycle reacted badly to L-theanine when we thought it would have helped to calm the CNS down.

For the past couple of months, I've been struggling to drink 1 or 2 cups of green tea a day (I find the taste unpleasant, even when I mask it in a brew of other types of tea) and I don't think I feel better on any health dimension from drinking it (although I can't know what it might be doing internally-fighting potential cancer etc.), and when I applied it to my face as a toner once daily over 2 days, it stung and dried out my skin, so I'm not sure that green tea is for me. I would like to stop drinking it... I've read such overwhelmingly-positive reports of its health-giving properties that I was interested to learn here that it inhibits the production of BH4 (via DHFR). Yesterday I read that it reduces the absorption of thiamin (B1) and folate (B9), plus of course iron.

 

[nandixon]

Valentijn, I believe that you misunderstood what NanDixon said about Richvank's results.

You have indicated in your table here that Rich's result for rs1650697 was AA. However, that is what NanDixon said HER result was. She stated that rs1650697 was the only one where she differed from Rich's.

She also stated that Rich's results were all homozygous and all "-/-", so that probably means that Rich's result on rs1650697 was GG, the only other possibility if NanDixon's "+/+" AA homozygous result was different from his.

In her original post, she wrote: "....his results appear to be completely normal (homozygous -/- throughout). Mine are identical to his with only one exception: the SNP rs1650697 (aka C35T or G-437A) that overlaps with a coding region for the gene MSH3 is homozygous (+/+) for the variant alleles (AA)....
Below are my results for people to compare to theirs.... rs1650697 AA (+/+)."

I have not tried to search for the thread where Rich reported his original 23andme results, but that would be the best way to make sure, of course.

That's right. The post where Rich gave his SNPs for DHFR is located here:
http://forums.phoenixrising.me/inde...ies-please-post-here.14115/page-2#post-233836

 

[roxie60]

Mine are the same as Nan's except for the last one I am AG which means I am exactly the same as Drex. I look forward to the GCH1 thread.....if it already exists can someone add the link plz

 

[ukxmrv]

Here's mine but I am late to this thread and don't have a clue what it all means

rs7387 TT
rs1643659 TT
rs1677693 GG
rs1643649 TT
rs11951910 TT
rs865646 GG
rs13161245 --
rs10072026 TT
rs11490741 CC
rs863215 CC
rs1478834 CC
rs1650697 AG

 

[LynnD]

Mine are the same as Val's.
Anyone try food or supplements to see if beneficial for this snp's?

 

[trollo]

These are mine:

rs7387 A or T AT (+/-)
rs1643659 C or T CT (+/-)
rs1677693 G or T GT (+/-)
rs1643649 C or T CT (+/-)
rs11951910 C or T TT (-/-)
rs865646 G or T TT (+/+)
rs13161245 A or G no call
rs10072026 C or T TT (-/-)
rs11490741 C or T CC (-/-)
rs863215 C or T CT (+/-)
rs1478834 A or C AC (+/-)
rs1650697 A or G GG (-/-) p.s i corrected this as Valentjin made me do a mistake...

Please can somebody explain to me what that means?? Does this mean i could have low BH4 recicling via DHFR??

 

[trollo]

But i yet haven't understood if there are any known deleterious DHFR snps already linked with issues by studies.

 

[aquariusgirl]

Hmm, why would my mom only have 5 snps on that gene?

 

[Valentijn]

Hmm, why would my mom only have 5 snps on that gene?

Newer chip?

 

[Gondwanaland]

Interesting. My husband is +/- to many of these SNPs. He benefits from Royal Jelly instantaneously. I have always been puzzled by the fact that RJ does nothing for me since many of my SNPs point to BH4 deficiency.

nandixon's ; myself ; my husband
DHFR SNPs:
rs7387 A or T TT (-/-) not available
rs1643659 C or T TT (-/-) TT ; CT
rs1677693 G or T GG (-/-) GG ; GT
rs1643649 C or T TT (-/-) TT ; CT
rs11951910 C or T TT (-/-) n.a.
rs865646 G or T GG (-/-) GG ; GT
rs13161245 A or G AA (-/-) n.a.
rs10072026 C or T TT (-/-) n.a.
rs11490741 C or T CC (-/-) n.a.
rs863215 C or T CC (-/-) n.a.
rs1478834 A or C CC (-/-) n.a.
DHFR, MSH3 rs1650697 A or G AA (+/+; 4% frequency) AG ; GG

 

[Envista]

Hi nkm,

No, that's not right. 7,8-dihydrobiopterin (BH2) is recycled to tetrahydrobiopterin (BH4) by dihydrofolate reductase (DHFR).

A different molecule, quinoid-dihydrobiopterin (q-BH2), is recycled to BH4 by dihydropteridine reductase (DHPR).

So DHFR and DHPR both produce BH4, but in different regenerative/recycle pathways using different molecules as substrates.

DHFR is likely to be (much) more important than DHPR in CFS/ ME for a number of reasons, including as I alluded to in my original post the role of DHFR in regulating the ratio of BH4 to BH2 to help maintain endothelial nitric oxide synthase (eNOS) coupling, ie, to prevent damaging superoxide (free radical) and peroxynitrite production. There are a number of articles on this, including:
http://www.ncbi.nlm.nih.gov/pubmed/21402147/
("Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency" 2011)

Although DHFR does process folic acid, folic acid is not a naturally occurring substrate for that enzyme. It's a synthetic, man-made type of folate and actually inhibits the recycling of BH2 to BH4 by competing as a substrate for DHFR. (This is a good reason, among others, for people to avoid folic acid.) A recent article talks about this:
http://www.ncbi.nlm.nih.gov/pubmed/23707606/
("Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling" 2013)

Hi Nandixon, whilst this was posted a few years ago I see you're still an active member. You seem to really know your biochemistry. I have a question for you....

There are two ways to convert dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). I'm mostly interested in with the DHFR involvement and recently attended a seminar on "Methylation". They suggested that BH4 is 'methylated', thus a carbon group (CH3) is added to BH2 to make BH4. To quote specifically from the manual provided: "by donating a methyl group from folate to create tetrahydrobiopterin (BH4), used for the synthesis of certain monoamines". However upon hours of internet research I haven't found that to be true, I've only found that Folate (in the form of THF) donates a Hydrogen to BH2.

I'd be interested in your opinion. Thanks.

 

[alicec]

To quote specifically from the manual provided: "by donating a methyl group from folate to create tetrahydrobiopterin (BH4), used for the synthesis of certain monoamines

That's not correct. The enzyme DHFR is a reductase not a methyl transferase; electrons (in the form of hydrogen) are transferred, not single carbon units.

The names of the substrates and products give the answer. Dihydrofolate is converted to tetrahydrofolate, dihydrobiopterin is converted to tetrahydrobiopterin. The reduced substrates, ie the products of the reduction reaction, have two additional hydrogens.

 

[Envista]

That's not correct. The enzyme DHFR is a reductase not a methyl transferase; electrons (in the form of hydrogen) are transferred, not single carbon units.

The names of the substrates and products give the answer. Dihydrofolate is converted to tetrahydrofolate, dihydrobiopterin is converted to tetrahydrobiopterin. The reduced substrates, ie the products of the reduction reaction, have two additional hydrogens.

Actually if you go to http://www.altmedrev.com/publications/13/3/216.pdf Figure 4 you'll see that 5MTHF (activated form of Folic acid) converts to Methylene THF to form BH4, the difference in structure is one less hydrogen on Methylene THF. So whilst a 'Methyl group' wasn't transferred, 5MTHF seems to have donated a hydrogen and is certainly involved. The second figure on Figure 4 shows THF converting to DHF in the production of BH4 - what's occurred here?

Interestingly the article also states 5MTHF is similar in molecular structure to BH4 and can substitute for it in low BH4 conditions, "The chemical structures of BH4 and 5-MTHF are similar enough that eNOS will accept 5-MTHF as a substitute cofactor (Figure 5).39 A similar mechanism might be at play in the antidepressant effect of folate. This author hypothesises that 5-MTHF might substitute for BH4 in the hydroxylase enzymes involved in monoamine neurotransmitter synthesis".

So judging from a manual I was given during a Methylation seminar, we can definitely agree the following is incorrect, "5MTHF donates it's methyl group for the creation of BH4"

 

[nandixon]

Actually if you go to http://www.altmedrev.com/publications/13/3/216.pdf Figure 4 you'll see that 5MTHF (activated form of Folic acid) converts to Methylene THF to form BH4, the difference in structure is one less hydrogen on Methylene THF. So whilst a 'Methyl group' wasn't transferred, 5MTHF seems to have donated a hydrogen and is certainly involved.

The upper part of Figure 4 is showing the transformation of "qBH" into BH4 by having the MTHFR enzyme run in reverse. qBH2 is quinoid-dihydrobiopterin, which is a very similar but different molecule than dihydrobiopterin (i.e., BH2). (Note that the structure of methylene-THF actually has 2 less hydrogens than 5-MTHF. The loss of the other hydrogen just isn't being shown in the cartoon figure.)

For more about MTHFR running in reverse, see this old post of mine:
http://forums.phoenixrising.me/inde...sive-cbs-ammonia-fix.31835/page-2#post-500142

The second figure on Figure 4 shows THF converting to DHF in the production of BH4 - what's occurred here?

In the lower part of Figure 4, this is just showing the recycling of BH2 to BH4 by DHFR. (The diagram is also indicating that qBH2 can spontaneously rearrange to form BH2, which is correct.)

 

[alicec]

Figure 4 you'll see that 5MTHF (activated form of Folic acid) converts to Methylene THF to form BH4,

@nandixon just answered, so I'll simply add the following.

As far as I am aware, that single in vitro study by Kaufmann is what everyone relies on to claim that MTHFR runs backwards. That was in an artificial laboratory creation. There is no evidence that it does this in the body and if you look at any text book or general article on the folate cycle you will see that the MTHFR reaction is one of the forward only reactions in the cycle (some other parts can go in two directions depending on cellular circumstances).

I've uploaded a diagram to illustrate this.

Here is an older post of mine which discusses a number of inaccuracies in the article you linked.