The NO/Urea Cycles

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Biopterin (BH4) is a critical cofactor for synthesis of key neurotransmitters and hormones. However it is also an important cofactor for the Nitric Oxide (NO) cycle, and we need enough biopterin from folate to support both processes.

NO is a reactive free radical which acts as a biological mediator in several key processes. Mostly it acts as a vasodilator and anticoagulant in blood vessels, so affecting blood circulation. This is important for getting nutrients and oxygen to tissues, increasing energy, supporting immune function, and removing waste products from cells. Too little NO may result in poor circulation, hypertension, low energy, and even erectile dysfunction. NO also acts as a neurotransmitter, and has anti-microbial and anti-tumour effects. Overall, appropriate levels of NO are vital to good health.

The nitric oxide cycle closely relates to the urea cycle too - a necessary waste disposal system the body uses to breaks down ammonia in the liver and kidneys and excrete it as less toxic urea. This also helps to reduce acidity in blood, and maintain pH. 

The common link between these 2 cycles is the amino acid arginine. As part of the breakdown of ammonia to urea, arginine is formed. Some of that arginine is used as the substrate for the NO cycle.


The key enzyme here is NOS (Nitric Oxide Synthase), specifically endothelial NOS (eNOS aka NOS3). How does this link to biopterin? The main cofactor for eNOS is BH4. Once nitric oxide has been synthesised, the breakdown product is citrulline which can then be recycled back to arginine.

SNPs in NOS3 can result in reduced circulation, energy, high blood pressure, blood coagulation, and erectile dysfunction. This could be compounded by insufficient BH4 made from folate cycle activity, or even a lack due to high stress response using it up for neurotransmitter and hormone synthesis. Insufficient BH4 can also tip the ‘pendulum’ of the NO cycle away from nitric oxide production towards making superoxide and peroxynitrates, highly reactive free radicals with deleterious effects on cardiovascular health and nervous tissue.

High ammonia can also overload the system. Although it initially sounds paradoxical (as higher ammonia should increase supply of arginine...), in fact it overloads the pathway, especially if eNOS function is reduced, up-regulating the arginase pathway of the cycle and converting as much arginine as possible to urea as an 'escape route'. This can happen to excess, stealing arginine from the NOS pathway. Other factors that could increase ammonia include a high protein diet, and a fast CBS enzyme in the Transulphuration pathway.

To support NOS3, we need to increase levels of BH4 by optimising production of 5-MTHF, bearing in mind this is also needed for NT synthesis and methylation. So reducing stress, toxic load, especially high levels of ammonia, and excess oxidative stress are also very important. Supplements of antioxidants, in particular vitamin C and glutathione, may be useful, as well as supporting the Superoxide Dismutase enzyme with manganese, especially if SOD SNPs are present. Nitric oxide can also be directly supported by eating foods rich in, or taking supplements of, arginine, citrulline and nitrates. The best example of high nitrate food is beetroot, so concentrated beetroot juice can be useful. Avoid supplementing arginine in certain situations where it can make things worse, such as herpes, asthma or low blood pressure. 


Bradykinin Receptor Beta 2 works with NO in supporting vasodilation by binding to kinin receptors. It is triggered in certain situations that would require an increase in circulation such as trauma or inflammation, and causes blood vessels to dilate, blood pressure to fall, and stimulates uptake of glycogen by skeletal muscle. BDKRB2 SNPs actually result in a positive health outcome, and increase sensitivity, so less bradykinin is needed to stimulate vasodilation, and improve circulation and oxygenation. This might compensate for any eNOS issues to an extent (although still better to support eNOS if needed). When BDKRB2 is ‘normal’, this is the less advantageous version, and may result in limited activity.  In this case we need to optimise our NOS function as mentioned before, perhaps also ensuring a good level of aerobic activity as well to boost circulation.

People think methylation is complicated, but we hope these articles have helped you not to fear it. The Lifecode Gx®️ Methylation Report is an invaluable tool to help you understand the underlying processes. Remember to keep things simple and look at the main patterns. The foundation of all of this is getting the folate and methionine cycles working, so checking out issues there is a great place to start. They can always be improved by simple dietary and lifestyle changes and perhaps methyl folate, vitamin B12 and other cofactors as supplements if needed. Over and above those fundamentals, you can also create more personalised support for a client by taking on board some of the other tips we’ve mentioned for each particular SNP.

Good luck making a difference with the magic of methylation! 

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