Terma
Member
- Joined
- May 8, 2017
- Messages
- 1,063
A dNA search engine confirms RORα response element within niacin N-methyltransferase gene, yet it also has domains many more transcription factors. I had restricted the search to transcription factors that I knew something about, and what I'd excluded are: c-rel, HIF-1, STAT3, Sp1, ERα, etc. Included in the gene sequence are: YY1, RORα, PPARγ, RARα, AP-1, AhR, and the glucocorticoid receptor (GR). [Link 'saved for 7 days.']
Interesting it's responsive to RAR (since RA also affects methylation cycle metabolites through GNMT).
Given your link (7 days = perfect) I assume you meant PPARalpha, which is also interesting since it's related to the starvation response in liver.
No way I'll connect this today, but more clues.
Interesting idea. The only issue I have with that is that according to Nicotinamide: A double edged sword - ScienceDirect , methylation of nicotinamide prevents it from leaving the brain (thought to contribute to Parkinson's):Perhaps the methylation has more to do with solubility than anything? The N-methyl group of niacin could increase its penetrance into nervous tissue, and could potentially effect transmembrane flux. Yet, if this were the intention a person could rightly assume that O-methylation would be more effective as this would neutralize niacin's negative charge. However: since niacinamide is already neutral and the amide nitrogen makes O-methylation impossible, the N¹-methylation might appear an intuitive contrivance to increase niacinamide lipid-solubility. Would this N¹-methyl group enhance brain uptake? while transporting one methyl group per niacinamide to the brain for increased cholinergic activity & myelination? However: the fact that niacin has actually been shown to increase cerebrospinal fluid homocysteine concentrations—albeit at massive doses—might imply that N-methylniacinamide does not effectively contribute to cerebral methionine formation. Nonetheless; this enzyme had evolved under natural niacin concentrations, those log orders below those used by: '80s cardiologists, Humphry Osmond, @Amazoniac, and Abram Hoffer. Thus, it may still seem appropriate to imagine niacin N-methylation as a pharmacokinetic ploy that'd evolved with the intent of shifting the body niacin pool towards the muscle, brain, and peripheral nervous tissue. This idea also suggests increased adipocyte compartmentalization as well, which can perhaps be seen either as an intentional way of increasing oxidative metabolism there or merely as an incidental consequence of the more important and intentional CNS uptake.
I assumed he was focused on toxins exiting the brain (rather than entering). Do you think it behaves completely differently for NMA going from body->brain? Fraid I haven't studied this much.Once charged with the N-methyl group, no toxin can cross the blood/brain barrier, so the toxication step has to take place in the brain. The enzyme NNMT has recently been shown to be present in the brain of humans [26] and rats [27]. The enzyme’s activity, protein and RNA levels are increased in the brain of patients with PD [26,28].