Pyrimidine Biosynthesis (UMP, uridine)

[Tunguska]

https://en.wikipedia.org/wiki/Pyrimidine_metabolism - Pathway that produces UMP (uridine) in the body.

I'm sure I'm not the first, but I brought this up here: http://forums.phoenixrising.me/index.php?threads/b2-i-love-you.15209/page-40#post-492735

I'd been trying a sublingual UMP+ omega-3 + choline stack with noticeable results. It's clearly propelled by the UMP, with choline from food or bitartrate sufficing. It produces focus and sense of well-being, almost as though my frontal cortex is waking up from the dead. Unfortunately supraphysiological doses of UMP are too risky because it seems to have side effects for me.

Most interestingly I was able to replicate it using ~30mg doses of R5P form of Riboflavin with roughly the same prerequisites (which, are, basically, a protein meal an hour before; other cofactors I'm still working out since I take many). Practically the same effect as UMP, but less intense. In fact I scored nicely tonight, I feel like an actual person and am using the energy to make this thread.

The R5P/FMN is a cofactor in pyrimidine synthesis: https://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase . Just speculating perhaps it was making uridine from my protein meal.

Uridine seems to be an important factor in every one of my issues. Maybe instead of supplementing it, it might be wise to support natural pyrimidine synthesis?

That's where I need some help. Does anyone know or know how to identify all the cofactors in these pathways?

What should you do to keep it running smoothly?

All I could identify were R5P/FMN and NAD as cofactors. Glutamine is an input according to most sources (there was one source that listed glycine as an input - http://www.ninds.nih.gov/research/parkinsonsweb/cinaps/Compound Dossiers/Triacetyluridine dossier.pdf - is that an error?). Is it worth supplementing additional glutamine? I already have but I couldn't tell if it had any effect other than it was not sufficient as a sole protein source.

I also understand the gut is involved; am working on that.

Apologies, I wasn't able to upload these:
http://www.udel.edu/chem/white/teaching/CHEM642/PyrimidineBiosynthesis.gif
http://www.namrata.co/wp-content/uploads/2013/02/steps-of-de-novo-pyrimidine-biosynthesis.png

 

[Tunguska]

I'm starting to think it might be futile to try to find cofactors experimentally. It seems to need everything. Maybe that makes sense because the synthesis takes ATP as input. So you need to have krebs working (possibly extra hard?), to make uridine. So the cofactors would be, everything in krebs at the least, perhaps in relatively high doses, I dunno. Then the cofactors that are also part of the synthesis itself need extra amounts.

Just as a disclaimer, I can't know for 100% sure that the effect I feel is from UMP synthesis, but it was a distinct feeling I never got from other supplements except UMP and maybe the first time I took tyrosine. To notice UMP, along with the meal you definitely need some tyrosine, choline, maybe Vit D or sunlight, maybe Vit C, maybe Folate, minerals, and other dopaminergic things (which on their own no longer have any effect on me). Then the UMP synthesis needs ATP/krebs, the urea cycle [edit: or something, idk lol] - protein (glutamine, aspartate), B2, maybe B3, maybe others that I ask here. So it's a lot of things that have to work. I don't think I'll be the one to put it all together but it does.

Also I don't know if I put this thread in the right place, but it's where the B2 thread was...

 

[aaron_c]

Kudos for research. I'm so glad you told me about uridine--I didn't know much about it.

If this study is right, uridine might help with more than neurotransmitters: One study called "Uridine triphosphate maintains cardiac mitochondrial function following chemical and hypoxic stress" ends by hypothesizing that "UTP may act as an uncoupling agent, which exerts a modest mitochondrial depolarization, resulting in a reduction of Ca(2+) uptake, preserving mitochondrial activity, thereby reducing cell damage during hypoxia." Since most of us with ME/CFS have too much Ca in our cells, this might mean that bringing uridine monophosphate levels up (and thereby raising UTP levels) would be helpful in protecting our mitochondria.

It seems like people with ME/CFS *might* have a problem with uridine synthesis beyond problems producing P5P (not to be confused with R5P). The rate-limiting enzyme in pyrimidine synthesis, dihydroorotate dehydrogenase (DHODH), exists in the mitochondria and "needs a functional respiratory chain" to work (I think because it needs CoQ10). Serum CoQ10 has been low in people with ME/CFS, and our mitochondria seem to be quite beat up, so it seems *possible* that this would cause a further block in the production of UMP. Hopefully, the asterisks have communicated that I am far from sure about this.

Does anyone know about nucleotide levels in people with ME/CFS?

 

[Tunguska]

If this study is right, uridine might help with more than neurotransmitters: One study called "Uridine triphosphate maintains cardiac mitochondrial function following chemical and hypoxic stress" ends by hypothesizing that "UTP may act as an uncoupling agent, which exerts a modest mitochondrial depolarization, resulting in a reduction of Ca(2+) uptake, preserving mitochondrial activity, thereby reducing cell damage during hypoxia." Since most of us with ME/CFS have too much Ca in our cells, this might mean that bringing uridine monophosphate levels up (and thereby raising UTP levels) would be helpful in protecting our mitochondria.

Good find. That does resonate with my issues - in particular reaction to a fluoroquinolone, known to be associated with Ca/Mg problems in cells. Usually people overdose on magnesium to try to counter the reaction, but there you might have a real mechanism to regulate the balance.

Uridine does seem to have quite a few roles in the body, even so far as hyaluronan synthesis in joints (http://www.ncbi.nlm.nih.gov/pubmed/18661323). Plus all the neurogenesis studies linked in nootropic resources. The general impression I got was that it was somewhat of a growth/repair agent not entirely unlike folate. Though that's probably too simplistic.

I should probably disclaim that it may have some downsides as well. If you look up the enzyme again, https://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase#Clinical_significance, one treatment for arthritis (Leflunomide) apparently works by blocking uridine production because large increases feed lymphocyte cells in auto-immune problems. So it definitely holds some power and like everything you can overdo it and it might not be for everyone. This is part of why I'm looking to find a more "natural" or evened-out way of increasing uridine.

Thanks for bringing this up. You may be a better researcher than I am so every bit helps.

 

[Tunguska]

Just to clear this up, the post http://forums.phoenixrising.me/inde...sive-cbs-ammonia-fix.31835/page-2#post-498054 was meant for this thread.

Another possibility is the chicken (and sardines) is high in niacin. Didn't suspect it because I was already taking nicotinic acid (40mg usually but tried up to 400mg) and its contribution was doubtful. But recently tried higher doses of niacinamide along with R5P and it had a clear contribution although also somewhat sedating in those amounts. Tough to say.

 

[nandixon]

It seems like people with ME/CFS *might* have a problem with uridine synthesis beyond problems producing P5P (not to be confused with R5P). The rate-limiting enzyme in pyrimidine synthesis, dihydroorotate dehydrogenase (DHODH), exists in the mitochondria and "needs a functional respiratory chain" to work (I think because it needs CoQ10). Serum CoQ10 has been low in people with ME/CFS, and our mitochondria seem to be quite beat up, so it seems *possible* that this would cause a further block in the production of UMP. Hopefully, the asterisks have communicated that I am far from sure about this.

I'm sure you're correct about this. A deficiency of coenzyme Q10 is going to be a problem for uridine synthesis.

That was shown in the following 2007 study:
Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis

The authors were looking at a defect in the COQ2 gene, but their finding is going to apply to defects in other CoQ10 synthesis genes (e.g., PDSS2), and to most states of CoQ10 deficiency, I would think:

Moreover, we demonstrate that the pathogenesis of CoQ10 deficiency is related not only to a defect in bioenergetics [e.g., ATP production], but also to an impairment of pyrimidine metabolism.

And, importantly, it looks as though when supplementing CoQ10, to attempt to correct a deficiency, that it may actually be more difficult to correct the impairment in uridine synthesis than to correct the electron transport chain's need for CoQ10:

Surprisingly, the effect of uridine addition was even more pronounced than that of CoQ10 suggesting that this phenotype is largely due to an insufficient supply of nucleotides rather than to an impairment of ATP production. We believe that the relative lower efficiency of CoQ10 in rescuing the defect in proliferation is probably due to a low efficiency of its incorporation in cells (1,23).

To me this implies the possibility that for people who are deficient in CoQ10, some of us may not be able to tolerate what may be very high levels of supplemented CoQ10 necessary to have sufficient synthesis of uridine (which is used to make RNA, for example).

More than a total of 400mg per day (200mg at breakfast and lunch), makes me very uncomfortably wired, but still tired. I needed to take at least double that amount to feel more energy and have less PEM - but be even more wired.

Some people, like @SOC and @jeff_w, seem to need as much as 1200mg to maximize the benefits of CoQ10, if I recall correctly. But many people may have intolerable side effects at that level.

So it may be that those people can overcome a possible intracellular functional deficiency of CoQ10 (with respect to pyrimidine synthesis) by using lower doses of CoQ10 but also supplementing with either uridine or CDP-choline (a precursor to uridine).

I just started trialling both 5'-uridine monophosphate and triacetyuridine (no results to mention yet), and I'm planning to try CDP-choline as well.

I'm looking at this because I began thinking that perhaps PEM is in part related to reduced gene expression, i.e., reduced transcription of DNA to RNA. And uridine is needed to make RNA.

 

[futuritycarpaccio]

just wanted to add this thread here, maybe it helps you:

http://www.longecity.org/forum/topic/51802-gpc-choline-uridine-dha/

It's one of the largest threads on longecity and I was meaning to try this and found your thread by chance.

 

[Tunguska]

Thanks. I've followed that thread but worth a look anyone who hasn't. They list a number of cofactors, many of which I was taking when this thread was created.

I believe uridine is one of the more important chemicals and I still get some effects from occasional use, but it doesn't relieve my current worst issues significantly, nor does R5P/folate, so the experiment that sparked this thread is on hold indefinitely.

Didn't have much to add to nandixon's good comments except to say I tried all 3 (UMP, TAU, CDP-choline) and sublingual UMP had by far the strongest effects, initially. CoQ10 used to be effective in high doses together with PQQ but rarely do I notice them anymore.