Under inflammation a number of changes happen to put your body into an inflammatory state similar to a see saw. One of those changes is the lowering of Tetrahydrobiopterin (BH4). Under conditions of oxidative stress, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals including superoxide and peroxynitrite. This is mainly due to the reduced uptake and availability of zinc during inflammation/infection.
Guanosine 5′-triphosphate cyclohydrolase-I(GTPCH-I), encoded by the GCH-I gene, is the rate-limiting enzyme in BH4 synthesis. ..Continuing along the de novo BH4 synthesis pathway, H2NTP is next converted to 6-pyruvoyl tetrahydropterin by the zinc-dependent enzyme, PTPS. Although GTPCH is rate limiting to BH4 synthesis in most cells, PTPS has been suggested to be rate limiting in some, most notably human hepatocytes. PTPS may become rate limiting in other tissues and cells, after stimulation with cytokines and other immunological stimuli that induce BH4 synthesis by up-regulation of GTPCH expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038990/
The PPAR-α agonist Fenofibrate upregulates Tetrahydrobiopterin (BH4) level through increasing the expression of Guanosine 5′-Triphosphate Cyclohydrolase-I (GTPCH) in human Umbilical Vein Endothelial Cells. Guanosine 5′-triphosphate cyclohydrolase-I(GTPCH-I), encoded by the GCH-I gene, is the rate-limiting enzyme in BH4 synthesis.
https://www.hindawi.com/journals/ppar/2011/523520/
All PPAR agonists tested lost their potency to downregulate the TNF-α–induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-α–mediated induction of inflammatory transcription factors NF-κB and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6
https://www.sciencedirect.com/science/article/pii/S0022316623029346?via=ihub
Our previous study demonstrated that homocysteine impairs coronary artery endothelial function by decreasing the level of BH4 in patients with hyperhomocysteinemia. Our previous study also showed that plasma level of BH4 was significantly increased by PPARα agonist fenofibrate in patients with hypertriglyceridemia
https://journals.physiology.org/doi/full/10.1152/ajpendo.00367.2010
Homocysteine has recently been found to be a competitive inhibitor of the nuclear transcription factors: Peroxisome proliferator activated receptors (PPARs) alpha and gamma
https://link.springer.com/article/10.1186/1475-2891-3-4 Homocysteine that rises from that not only increases ER Stress but also NLRP3 inflammasome activation as well from the studies mentioned before in other posts of mine so it seems its all part of the shift to an inflammatory state. Note also that zinc deficiency induces the itaconate shunt which inhibits B12 and therefore blocking methylation pathway subsequently increasing homocysteine so it all again is a shift to an inflammatory state.
Tetrahydrobiopterin (BH4) is a critical cofactor for the rate limiting enzymes in the synthesis of the monoamine neurotransmitters. BH4 is necessary for the conversion of phenylalanine to tyrosine by PAH, tyrosine to L-DOPA by tyrosine hydroxylase (TH) leading to the production of dopamine and norepinephrine, and tryptophan to 5-HTP leading to the production of serotonin.
Zinc regulates iNOS-derived nitric oxide formation in endothelial cells. Zinc inhibits iNOS-dependent nitrite accumulation in endothelial cells. Zinc decreases cytokine-induced iNOS expression in endothelial cells. Zinc inhibits iNOS promoter activity. NF-kB silencing abolishes cytokine-induced iNOS expression. Zinc inhibits the transactivation activity of NF-κB. https://www.sciencedirect.com/science/article/pii/S2213231714000834
Active vitamin B6 (PLP, pyridoxal 5'- phosphate, P5P) not pyridoxine https://pubmed.ncbi.nlm.nih.gov/21797845/ which is also dependent on zinc normally. The question remains if taking zinc such as zinc glycinate and active b6 work during high inflammation to restore balance, or need something else first or at same time to lower inflammation/nlrp3 overactivation to allow zinc and b6 availability to resume.
Hydroxocobalamin has different effects than Methylcobalamin and adenosylcobalamin so keep that in mind. Hydroxocobalamin (OH-Cbl), cobinamide, and dicyanocobinamide (CN(2)-Cbi) potently inhibited all Nitric Oxide isoforms NOS1, NOS2, and NOS3, whereas cyanocobalamin, methylcobalamin, and adenosylcobalamin had much less effect. https://pubmed.ncbi.nlm.nih.gov/19328848/ The extracellular NO scavenger hydroxocobalamin prevented the NMDA-induced release of glutamate providing indirect evidence that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining the NMDA receptor activation in a cGMP-independent manner. https://link.springer.com/article/10.1007/BF02976435 
