Dan,
Some papers regarding TMG and CBS:
Vitamin B-6 is a cofactor for CBS, and
50% of subjects with homocystinuria are responsive to vitamin B-6 therapy. ...
betaine... improves clinical symptoms, reduces homocysteine, and increases plasma methionine, serine, and cysteine concentrations (208221). ...Betaine treatment in children significantly lowers homocysteine in cerebrospinal fluid and raises serine and SAM concentrations (222). Studies on MTHFR deficiency (223230) showed that betaine improves homocysteine remethylation, lowers plasma homocysteine, normalizes very low plasma methionine, elevates SAM, and leads to clinical improvement. A defect in cobalamin-C (vitamin B-12) activation results in methylmalonic acidemia and homocystinuria, and treatment with cobalamin, folate, or vitamin B-6 does not completely correct the biochemical defect. Addition of betaine leads to normalized homocysteine and clinical improvement (231234).
In mice with moderate homocysteinemia caused by a disruption in the CBS gene, betaine supplementation decreases homocysteine, increases liver betaine, and increases BHMT activity in both heterozygous and wild types (252).
CBS contains heme (so iron status likely affects it):
http://www.nature.com/emboj/journal/v20/n15/abs/7593888a.html
Cystathionine -synthase (CBS) is a unique heme- containing enzyme that catalyzes a P5P-dependent condensation of serine and homocysteine to give cystathionine.
The heme part may not be correctable:
http://www.sciencedirect.com/science/article/pii/S0002929707610623
... All five cbs mutations formed substantially more aggregates than did the wild-type CBS, and no aggregates contained heme. These data suggest that abnormal folding,
impaired heme binding,...may be common mechanisms in CBS deficiency.
Never fear, TMG does the trick if you do not respond tp P5P:
http://journals.lww.com/geneticsinm...ne__beta__synthase_deficiency__Effects.3.aspx
Betaine improves metabolic control in B6-nonresponsive patients with homocystinuria after optimum dietary control.
CBS is susceptible to oxidants (but Yasko reported that). One such study with peroxynitrite:
http://www.sciencedirect.com/science/article/pii/S0003986109002860
So anti-oxidants are extremely important if you have the CBS mutation!
Here's an interesting study showing some other possibilities for help in the future for some CBS mutations through
agents that cause proper folding of the CBS enzyme. Also interesting statement here is that
yeast with CBS CANNOT GROW in a cysteine-free medium. As in with CBS, cysteine becomes a serious dietary need:
http://www.sciencedirect.com/science/article/pii/S1096719207001369
...mutations in the cystathionine beta-synthase (CBS) gene, ...are responsible for CBS deficiency, the most common inherited disorder in sulfur metabolism. Expression of human mutant CBS proteins in Saccharomyces cerevisiae reveals that most disease causing mutations severely inhibit enzyme activity and
cannot support growth of yeast on cysteine-free media. Here, we show that the osmolyte chemical chaperones
glycerol, trimethylamine-N-oxide, dimethylsulfoxide, proline or sorbitol, when added to yeast media, allows growth on cysteine-free media and causes increased enzyme activity from ...other mutant CBS proteins. ...This effect is not specific to yeast,...our data show that
chemical chaperones present during the initial folding process can facilitate proper folding of several mutant CBS proteins and suggest it may be possible to treat some inborn errors of metabolism with agents that enhance proper protein folding.
I ran across this interesting study - nothing to do with CBS exactly, but it shows a list of
antioxidants that prevented rise of homocysteine in aging (normal) rats - we'd have to figure out what the dose woul be for people and see where we stack up on our supplementation regimes (
I thought I read once that all CFS have lowered production of DHEA-S): http://www.sciencedirect.com/science/article/pii/S0304394010010128
The study has shown that in aged (2224 months) rat brains an elevation of homocysteine level (42%) and a decrease in dehydroepiandrosterone sulphate (DHEA-S) content (32%) occur compared to those in the brains of young rats (46 months). Such changes in the brain levels of homocysteine and DHEA-S in aged rats are prevented, when the diet daily of the rats is supplemented with a combination of antioxidants
(N-acetyl cysteine 50 mg, ?-lipoic acid 3 mg and ?-tocopherol 1.5 mg each per 100 g of body weight) starting ...The brain content of reduced glutathione is also decreased in aged rats as compared to that in young ones and the phenomenon can again be prevented completely by the same regimen of antioxidant supplementation. ...
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2010.06606.x/full
This study is interesting because it brings something new into the mix: apparently
CBS makes H2S which is one of 3 gasses modulating the H-P-A axis. Hmm, it says here H2S is made in brain which would contradict a previous study saying the CBS pathway does not exist in brain (I'll haveto track that down). Basically it says
H2S calms down the inflammation hyper response of the HPA (lack of which which is probably what burned out your adrenals). I am going to try and see if DMSO seems to affect this (I will have to buy a new bottle). I don't know if that sulfur can combine to form H2S, but if so -- an adrenal protection bonanza there. It does deflate inflammation noticeably (like fast enough that you can see it happen).
The above paper is of further interest because it says: "
CBS activity in the brain is calcium/calmodulin-dependent".
For that assertion, here is the paper cited:
http://www.ncbi.nlm.nih.gov/pubmed/...+5+Nov+from+10-12+GMT+for+monthly+maintenance
New roles for cysteine and transsulfuration enzymes:
production of H2S, a neuromodulator and smooth muscle relaxant.
Dominy JE, Stipanuk MH.
And re: calcium/calmodulin, I also find this:
http://www.ncbi.nlm.nih.gov/pubmed/12213817
A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase.
Eto K, Kimura H.
CBS (3 regulatory domains activated by p5p, SAMe and redox [13])
HEY - BINGO YOURSELF HERE -- NOTE THAT TESTOSTERONE INDUCES CBS ACTIVITY (so it is not just estrogen that positively affects the methyl cycle!) see below
CBS activity is induced by SAMe (via enzyme stabilisation) [14], testosterone [15], vitamin D [16], and by neuronal Ca2+/calmodulin [17,18]. CBS is modulated via redox (fe(III) & CO) [13,19] and notably inhibited by peroxynitrite [20[/B]
H2S is produced from cysteine by cystathionine beta-synthase (CBS) in the brain and functions as a neuromodulator. Although the production of H2S is regulated by Ca2+ and calmodulin in response to neuronal excitation, little is known about the molecular mechanism for the regulation in CBS activity. ...
Wiki says of calmodulin: CaM mediates processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, nerve growth and the immune response. ...Many of the proteins that CaM binds are unable to bind calcium themselves, and as such use CaM as a calcium sensor and signal transducer. ...CaM can bind up to four calcium ions, and can undergo post-translational modifications, such as phosphorylation, acetylation, methylation and proteolytic cleavage, each of which has potential to modulate its actions. Calmodulin can also bind to edema factor toxin from the anthrax bacteria.
SO I did a little search of Vitamin D since you say you have the Vitamin D receptor defects as I do and I found this:
http://www.clinsci.org/cs/120/0099/1200099.pdf
...vitamin D...up-regulates expression of metallothionein, a free radical scavenger protein with photoprotective properties [120].
(I take 7000 mg D/day)
The enzymes of the transsulfuration pathway also have the capacity to catalyze the desulfhydration of cysteine. Recent studies demonstrate a role of the transsulfuration enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, in catalyzing the desulfhydration of cysteine in brain and smooth muscle. The H2S produced from cysteine functions as a neuromodulator and smooth muscle relaxant. In glutamatergic neurons, the production of H2S by cystathionine beta-synthase enhances N-methyl-D-aspartate (NMDA) receptor-mediated currents. In smooth muscle cells, H2S produced by cystathionine gamma-lyase enhances the outward flux of potassium by opening potassium channels, leading to hyperpolarization of membrane potential and smooth muscle relaxation.
I see there is already a CFS site that knows about the effect of calmodulin, If you are not aware of it you may want to take a look: http://bb-cfs.blogspot.com/2010/07/methylation-pathway-regulation.html
I'm sorry I don't have the kind of time I've had in the past to go over studies. I think the above is useful for someone who doesn't know much about CBS (like me), not so sure about you. I just followed Fredd's protocol and got my homocysteine perfect and figured the gene was therefore not a problem since I could do it.
Regards,
Rydra