Gout Uric Acid
I’d like to add gout as another area that Dr. Kats can give us advice on. Gout causes problems for a... View more
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Reply To: Gout: Try, Try Again
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Okay, so let me give you the breakdown of how the original 3:1 Glutamine:Flush Niacin mass ratio was conceived, and how it was quickly changed:
Per sub-Figure D below, from the following paper:
Glutamine-dependent NAD+ Synthetase: HOW A TWO-DOMAIN, THREE-SUBSTRATE ENZYME AVOIDS WASTE
https://www.jbc.org/article/S0021-9258(20)70523-5/fulltext
…Intuitively, after examining the results of this study, particularly sub-Figure D (picture attached below), it would be conceivable that the whole key would simply be to meet & continue meeting at least the minimum concentration of ~125 mM glutamine in every cell dynamically forward (sub-Figure D), corresponding to niacin at at least pharmacological doses to continue to make at least 600 uM NaAD+ intracellularly, which equates to accordingly, 600 uM flush niacin, given 1 niacin makes 1 NaAD+ (so 1:1 mole of niacin:NaAD+). Dividing glutamine’s then 125 mM concentration by (1 mole niacin to make 1 mole NAaD+,
so 1 *) 600 uM for that of niacin’s, gives a respective 2.5 (glutamine) to 1 (niacin) as the molar ratio of niacin to glutamine, in turn explaining the originally devised mass ratio of glutamine to niacin as 3 to 1.Variability of glutamine concentration across the body’s cells (coming into this co-supplementation upon now realizing diet’s deficiencies and what that led to over life to this point) ranges from completely void to some measurable degree of lacking of at least that 125 mM depicted in sub-Figure D needed to be met (& maintained) to continue to efficiently.
Further, to most efficiently catalyze niacin’s de novo NAD+ biosynthesis (& everything beyond that then follows), all exogenous glutamine will be maximally converted to glutamate, assuming glutamine + niacin are dosed at adequately high-enough and at equimolar amounts, as this is what is depicted per this wonderful paper as the fashion in which flush niacin + glutamine enter each cell through the body in fact (see second pic below from this article):
A New Step in the Treatment of Sickle Cell Diseasehttps://pubs.acs.org/doi/10.1021/acs.biochem.7b00785
…
to have to be most favorable to occur then to assume this quaternary complex (depicted in second pic attached below) forward with niacin’s NAaD+ catalyzed by equimolar glutamine. Meanwhile, providing sufficient equimolar amounts of the two, in turn, to fuel NAD+ biosynthesis and beyond, will also be accomplished w/o any NH3 (ammonia) waste, assuming enough niacin is dosed to lead to cellular concentrations of 600 uM NAaD+.Moving forward, this glutamate that is formed with sufficient + equimolar glutamine + niacin doses, becomes optimally powered to proceed thereafter to glutathione and to the citric acid and beyond, powered by flush niacin going to NAD+ (and redox.. & beyond), to ultimately make ATP, by way of the restoration of (above paper’s noted) NAD+/NADH/NADPH/NADP+ redox along with NAADP+/autophagy/T-cells/clearance of particles, as well as ultimately, the electrochemical balance. Moreover, for the first time, this will finally allow the NAD+ biosynthesis, fueled by sufficient amounts of the two in equimolar ratio as depicted, to power-glide all conversions of glutamine & intermediates forward, likely even—with enough dosing met—all the way around the citric acid cycle, synergized by well-balanced diet and enough clean (ideally distilled, not above room temp. water).
The quickly updated to now correct stoichiometric 1:1 molar ratio corresponds to a mass ratio of 1:1.187, i.e., 1 molecule of flush niacin to makes a corresponding 1 NaAD molecule (and is moiety of NaAD), which complexes with each 1 glutamine molecule in reaction, and so dividing glutamine’s molar masses by that of niacin’s, gets 1.187 times (in mass) as much glutamine as niacin in grams.
^ Hence, the previous 1:3 flush niacin:glutamine mass ratio was (3 divided by 1.187 =) 2.527 times greater glutamine (in mass) dose coming each time with flush niacin. This excess glutamine coming in (2.527x as much needed each time) with niacin, led to acute arousal of symptoms by way of then not having that needed niacin with it to turn to NAD+ & beyond, and instead staying as glutamate and into glutamic acid out the cell, further depleting purines/DNA synthesis, and in this way, not being able to make glutamate properly to fuel purines synthesis without equimolar niacin alongside (as per the following recently published paper):
“We demonstrated that fructose promoted purine de novo synthesis to generate IMP and drive conversion of IMP to AMP to maintain the rapid depletion of ATP. Fructose increased the breakdown of preformed PNs and their derivatives (adenine, xanthine, and hypoxanthine), accelerated their degradation to UA [uric acid], and increased the serum UA level. This work revealed that increased purine de novo synthesis may be a crucial mechanism in fructose-induced hyperuricemia.
Conclusion: This study demonstrated that the increased purine de novo synthesis may be a crucial mechanism for fructose-induced hyperuricemia.”
Dietary intake of fructose increases purine de novo synthesis: A crucial mechanism for hyperuricemia
https://www.frontiersin.org/articles/10.3389/fnut.2022.1045805/full
…Now, check out this seminal paper (which note also how they used garbage extended/sustained release formulation of niacin, and not flush niacin (immediate release nicotinic acid), despite these curative effects reported for a similar process:
Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30190-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS155041312030190X%3Fshowall%3Dtrue…
Specifically glancing at Figure 5E (third pic attached below), we see how the lack of substrates/reactants to continue to achieve homeostatic purine synthesis is induced & augmented upon & over, respectively, the niacin deficiency (and ultimately, with niacin’s deficiency, we then learned, with glutamine’s alongside it; but as explained here, glutamine depleting alongside with flush niacin in a 1:1.187 & not originally conceived 1:3 mass ratio).Among many other key components, (albeit not folate or even flush niacin itself, given we need glutamine alongside), niacin restored IMP (even solo, underpowered without compensatory equimolar (i.e., 1.187x as much as niacin,) glutamine, and as the inferior, hepatotoxic, while also glycemic control-incapable sustained/extended release formulation):
(E) One-carbon metabolism and associated pathways in patient muscle pre- and post 10-month niacin. Colored text, changed at baseline; red, increase; green, decrease. Circled metabolites, changed upon niacin; red, increase; green, decrease. SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; IMP, inosine monophosphate; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; GAA, guanidino-acetic acid; MTA, 5′methylthioadenosine; ROS, reactive oxygen species; THF, tetrahydrofolate, MTHFD, methylene-tetrahydrofolate dehydrogenase; dTMP, deoxythymidine monophosphate.“Niacin and NAM metabolism was among the most significantly changed pathways, as a proof of principle, as were the biosynthetic pathways for purine, pyrimidine, methionine, and glycine metabolism, and bile acid and protein biosynthesis (Figure 5B). PEO patient muscle has imbalanced nucleotide precursor amounts (Nikkanen et al., 2016), of which inosine monophosphate and adenosine of purine synthesis were brought back to control level by niacin treatment (Figures 5C and 5E).”
The high uric acid-related flare-ups of gout are stimulated by not only, prominently, fructose (when you are this (equimolar) niacin + glutamine deficient), but really anything that can bring them on by way of, for instance, fructose having to generate IMP to fuel its breakdown to fuel the extra ATP needed now in compensation for the decreasing availability of niacin + glutamine for (among so many other goodies, proper) purine synthesis over the growing properly addressed deficit of equimolar niacin + glutamine. Fructose and other compounds have to be sacrificed in this fashion to continue to fuel this needed ATP by way of fueling the synthesis into breakdown of purines to do this in order to try to achieve this ATP demand. In severely niacin + glutamine deficient conditions, we accumulate uric acid as less allanotin continues to be made (again, please refer to the third pic attached, Figure 5E) and hypoxanthine can’t be fueled by niacin’s NAD+ to make xanthine or uric acid to turn to it this way too. The participants in this trial were not that glutamine deficient (and thus also niacin in equimolar amount) as you (/individuals living with recurring gout) are, and so even intermittently-released “niacin” was able to cure their systematic mitochondrial myopathy, albeit after a year. They were borderline completely folate deficient at baseline, in fact, but still enough, thus glutamine too, to fuel “niacin” to curative effects demonstrated after a year of low (b/c the SR/ER “niacin” is hepatotoxic at high doses, unlike flush niacin, as we know) dosing.
As the purine synthesis and its metabolism–ultimately the energy metabolism–restore by way of properly (i.e., 1:1.187 mass ratio + via sufficient levels of dosing) addressing the causative agents’, flush niacin + glutamine’s, deficiencies together, these flare-ups and the entire condition disappears. We know we have a lot to make up to achieve this, but it is totally understandable to be wary now and build up with dosing. I completely get it.
With sufficient (whatever it is, but we expect to need a lot these days, especially with nagging gout) and exactly equimolar glutamine matched with flush niacin alongside, exogenous glutamine will react nowhere else first but with then flush niacin’s NaAD+ through the formation of the quaternary complex (second pic attached below), as uniting with niacin’s NaAD+ into and only by way of this arrangement, constitutes the most thermodynamically favorable (and ONLY) route for the system/body/host/human (for example) to recover. The lack into deprivation of these two into now not to a T addressing the need for flush niacin + glutamine to be restored sufficiently but in equimolar (1:1.187 mass ratio) amounts is how this happened in the first, second, third, … and now, Nth place.
Single doses of at least 5 g flush niacin + 5.935 g glutamine will be expected — maybe up to even double that at least once a day (with in complement, a lower dose earlier &/or later that day, or even wait 18-36 h for the next dose if you see you are needing these higher levels earlier, and so likely they need some extra time to fully process/metabolize through to prep the body ideally for the next one) — for a week to really get things going. This is again the exact same mechanism I was trying to express earlier, but did not have these intricacies ironed out just yet, I apologize) are to be expected again, but this time, they will NOT be coming with that extra 9.065 g of glutamine excess this time (as you did with a 5 g flush niacin + 15 g glutamine dose before per the incorrect 1:3 mass ratio initially conceived).
I am very eager to hear how the updated, correct 1:1.187 (equimolar) mass ratio of the two goes from whatever dose amount. I am just letting you know that the dose to really overpower this, mechanistically speaking, is going to need to hit these needed (relatively higher) levels. Please build up to comfort. It will be a very good sign if the low dosing where you are starting do not lead to any flare-ups, or they dissipate as you go forward/up with dosing. This is what I expect. Please keep me updated. Do not worry.
