The Biopterin Cycle
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5-MTHF is essential to methylation, but also has another very important job. It’s a cofactor for an enzyme called Tetrahydrobiopterin, biopterin, or BH4, for short.
Biopterin is a cofactor for enzymes used in the synthesis of some really important neurotransmitters and hormones that help to maintain mood, motivation, focus, and support stress response. It converts tryptophan to 5HTP, and so eventually promotes the 'feel-good' neurotransmitter serotonin, and then melatonin for promoting sleep. It is also used to convert phenylalanine to tyrosine and then tyrosine to l-dopa, so promoting dopamine, adrenaline and noradrenaline.
It is worth emphasising how important 5-MTHF from the folate cycle is. It is at the very top end of synthesising some of our key neurotransmitters and hormones that help maintain our engagement with the world and our ability to increase our responses when we need to. Potentially, if folate, and so BH4, is disrupted, we may have mood imbalances, be more susceptible to stress, poor memory and concentration, and sleep disturbances. BH4 also protects nerve cells from heavy metal toxicity and glutathione depletion. So, if there are issues with the folate cycle, there is already a significant potential issue with reduced BH4 that could result in the problems mentioned. The simple solution, before we look at other details, is to support the folate cycle, so there is sufficient 5-MTHF.
QDPR
In the process of neurotransmitter synthesis, BH4 donates two hydrogens and is converted to BH2. QDPR enzyme (Quinoiddihydropteridine reductase) then recycles BH2 back to BH4. In fact, this is where methyl folate is used as a cofactor, to 're-methylate' the BH2. QDPR SNPs may hamper this process even more, and may need to be supported by optimising supply of folate.
VDR
The synthesis of serotonin and dopamine is dependent on another nutrient - vitamin D. Therefore, certain vitamin D receptor (VDR) SNPs can lower serotonin and dopamine production. It can be even more important for people with VDR SNPs to optimise their vitamin D levels, potentially via a supplement.
PNMT
Another important methylation-dependent enzyme on this pathway is PNMT (Phenylethanolamine N-methyltransferase), which methylates noradrenaline to form adrenaline, and therefore plays a key role in regulating adrenaline production. Variants on PNMT slow its activity resulting in more noraradrenline relative to adrenaline, and that has been linked to hypertension. Supporting this SNP is about optimising methylation and SAMe.
COMT
COMT (Catechol-o-methyltransferase) is perhaps one of the best known enzymes/gene/SNPs! It is a vital methylation-dependent detoxification enzyme, that breaks down dopamine, adrenaline and noradrenaline when they are high, such as in stress response.
Slow COMT can result in a heightened and prolonged stress response, and symptoms such as irritability and hyperactivity. It might not always be bad of course. It might help to maintain higher levels of those stress hormones when needed, keeping us focused and our energy levels up. COMT also detoxifies other catecholamines, such as catechol-oestrogens, and so supports oestrogen balance. On the other hand, people with 'faster' (wild type) COMT types may detoxify those stress hormones too quickly, resulting in energy dips or mental fatigue. A slow COMT SNP can be supported by optimising SAMe (and reducing SAH which competes for the same binding site) and using magnesium which is an important cofactor. It might be useful to be a little more cautious with high dose methyl donors, as they can sometimes increase the stress response. A low to moderate dose might work better and ensuring stress levels are reduced as well. For fast COMT, we need to optimise synthesis of neurotransmitters and hormones, via supporting the folate cycle, to keep them 'topped up'.
MAO
In a similar vein, the monoamine oxidase (MAO) enzymes are important for detoxification alongside COMT. MAO-A also helps to breakdown noradrenaline and adrenaline, along with serotonin and melatonin. MAO-B breaks down histamine, dopamine, tyramine and other amines. Both are relevant in various ways to supporting detoxification of stress-related hormones and may interact with COMT, with amplified effects if SNPs in both are present.
Slow MAO-A SNPs are associated with increased irritability and even aggression (sometimes referred to as the ‘warrior’ type). Similarly, slow MAO-B SNPs may result in excess dopamine, which can add to stress response. Support MAO enzymes by reducing stress, optimising COMT to help out, and use cofactors vitamin B2, magnesium and zinc. As with COMT, the faster ‘wild’ alleles might result in rapid breakdown of serotonin, dopamine, noradrenaline or adrenaline, which may result in fatigue, low mood, and even create dopamine dips that may feed addictive behaviour. You can support the faster SNPs by optimising synthesis of those neurotransmitters and hormones (biopterin) to keep them 'topped up'. Also MAO activity can be reduced using quercetin and curcumin.
There is even more detail on this, and many other factors, in the Nervous System Report, which is a great complement to the Methylation Report. However, you get some great information on some important and actionable SNPs in key neurotransmitters and hormones in the Methylation Report, and it can provide an excellent starting point to enable progress.