In the earlier post I focused on the two aspects of BH4 metabolism that Yasko discusses and pointed out where she had it wrong. To make that even more simple -
1) BH4 is a cofactor for the aromatic amino acid (phenylalanine, tyrosine, tryptophan) hydroxylases which are involved in neurotransmitter synthesis.
In these reactions, BH4 is converted to qBH2 which is then regenerated to BH4 by the enzyme DHPR.
MTHFR and methylfolate play no role in these reactions.
2) BH4 is also a cofactor for the enzyme NOS which converts arginine to nitric oxide (NO) plus citrulline. Ammonia is not involved in this reaction.
That is not the sum total of BH4 metabolism - there are several other aspects.
3) In the NOS reaction, if BH4 is limiting, the enzyme becomes uncoupled from substrate and generates superoxide. This radical can react with NO and generate peroxynitrile which perpetuates the uncoupling by oxidising BH4 to BH2 and so limiting it further.
This raises two additional considerations:-
a) Methylfolate is a peroxynitrile scavenger so can have a BH4 sparing effect and rescue the NOS reaction.
b) What determines BH4 availability?
4) BH4 bioavailability is determined by a complex balance of enzymatic
de novo synthesis and recycling, versus oxidative degradation within the cellular environment. The pathways are illustrated
here.
a) Three enzymes are involved in biosynthesis, the first of which, GTP cyclohydrolase 1 is rate limiting.
b) When oxidative reactions in the cell convert BH4 to BH2, the enzyme dihydrofolate reductase (DHFR) is used to recycle it back to BH4. qBH2 (produced in the amino acid hydroxylase reactions ) can spontaneously convert to BH2. When this happens, DHFR rather than DHPR recycles it to BH4.
5) BH4 is a cofactor for the enzyme glycerol ether monooxygenase which is involved in processing certain types of lipid into fatty acids.
So in brief form these are the metabolic pathways involving BH4.
The reactome site that you linked gives a good summary, shows the linkage of some of the metabolic pathways and gives references.
From this summary the take away message is that enhancing BH4 in the cell might be achieved in several ways - viz
by pharmacological supplementation, by enhancing the rate of de novo biosynthesis or by measures to reduce BH4 oxidation.
The latter is an important consideration, particularly if direct supplementation of BH4 is contemplated, otherwise this could be counterproductive and lead to more NOS uncoupling.