Core biochemical methylation pathways.

Two common mutations can cause decreased levels of BH4. The first mutation increases the activity of CBS, which converts Homocysteine to Cystathione and eventually to cysteine and then taurine.  The second mutation is directly involved in the regeneration of BH4 in the methylation pathway.

But before I get ahead of myself, why is BH4 so important?

Tetrahydrobiopterin (BH4) has five major responsibilities as a cofactor.  It is needed to work with:

Tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP)
Phenylalanine hydroxylase (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
Tyrosine hydroxylase (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
Nitric oxide synthase (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO) in the Urea Cycle
and
Alkylglycerol monooxygenase (AGMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol

The first three reactions are critical to producing adequate levels of serotonin and dopamine. Low levels of BH4 can impair neurotransmitter production and lead to the build up of toxic intermediates, like phenylalanine.



This chart shows that without BH4 phenylalanine (found in all foods) is not converted to tyrosine. Tyrosine one of the 22 amino acids used to build protein and is normally non-essential. It is found in most foods.

BH4 is synthesized in four ways:



BH4 is involved in the major biochemical cycles:



Methionine is a major source of sulfur groups in the diet, so limiting methionine-rich foods helps limit problems from an overactive transulfuration pathway (i.e. overactive CBS enzyme). Other sulfur rich foods include crucifer vegetables and onions and garlic.

BH4 is tangentially involved in both the urea cycle and the folate cycle.

The urea cycle in detail: Arginine from our diet or from protein metabolism is converted to ornithine and urea by the enzyme Arginase. Ornithine is then converted to citrulline by ornithine transcabamoylase (OTC). Citrulline is converted back to arginine. This cycling of Arginine through the various intermediates is what converts ammonia to urea. (More info)


Source.

Arginine is also required for the production of Nitric Oxide (NO) by the enzyme nitric oxide synthase (NOS or eNOS). This reaction is dependent on the levels of BH4 available from the BH4 cycle. Remember two molecules of BH4 are needed to generate Citrulline and NO. One molecule of BH4 will in turn generate peroxynitrite and if there is no BH4, super oxide is formed. (Source. )

The Urea Cycle and the Nitric Oxide Cycle are interconnected by arginine as follows: Citrulline, made from ammonia (and ornithine), is recycled to arginine in the Urea Cycle. That arginine can then enter the Nitric Oxide Cycle where it is converted to nitric oxide by nitric oxide synthase using tetrahydrobiopterin (BH4). (Note that citrulline is also generated during the formation of nitric oxide from arginine.)

From this we can conclude that a deficiency in BH4 does not impact ammonia detoxification in the urea cycle.

Important Nutrients in the Methionine Cycle

Graphic from the inimitable benbest.com.  GSH is glutathione.

Studies suggest that betaine, along with vitamins B6 and B12 and folic acid, helps reduce higher levels of homocysteine. (This article has lots of citations.)  I think there is now good evidence that the problem with methionine  is really a problem with homocysteine.  Having high levels of homocysteine is related to a higher risk of heart disease and stroke.  Food sources of betaine include beets, broccoli, grains, shellfish, and spinach.  More info on betaine.

Source.

Also note the importance of amino acids like cysteine, glycine, and serine: Cysteine and glycine are converted to glutathione (an important water-soluble antioxidant) with the addition of selenium.  Pea protein and collagen are good sources of glycine, but neither contains much cysteine.  Serine can reduce homocysteine levels, and pea protein is also a good source.

Comparative Physiology: Maximum Lifespan

A conundrum if the amino acid methionine is a determinant of maximum lifespan: Why do carnivores and vegetarians live the same? Perhaps it could be for different reasons.... antinutrients for the latter and methionine for the former. These are universal rules that apply even between disparate physiologies. I haven't been able to find any papers that examine methionine diet content versus longevity.

Source: Ecology and mode-of-life explain lifespan variation in birds and mammals, Proceedings of the Royal Society B, DOI: 10.1098/rspb.2014.0298

This is a valuable resource on important "carninutrients" lacking in vegetarian diets.  

New Paper Continues Confirmation of Age-Defying Diet

In the last 15 years a number of research groups around the world have converged on an explanation for how dietary restrictions can lead to lifespan extension. These teams have narrowed the search to a handful of compounds.*  The central candidate, by far, is an essential amino acid called methionine, found in high amounts in meat and fish, but in very low amounts in most plant foods.

Reducing consumption of this single amino acid extends lifespan by 15-44% in every laboratory animal tested to date. This effect is sufficient to completely explain previous results that found dietary restriction of total calories led to lifespan extension. Turns out it wasn't the calories -- it was the methionine.

Methionine restriction reduces visceral fat with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Methionine restriction also prevents age-associated increases in serum lipids.(source)

A new paper published this month by Koziel et al confirms previous methionine restriction results in human cell culture, mice, rats, fruit flies, and yeast. Koziel et al used human cell culture to specifically examine mitochondrial function and showed that oxidative stress is reduced by this dietary intervention.  This work supports the traditional free radical theory of aging-by-oxidative stress.

Methionine is an interesting amino acid because it promotes growth, including muscle and bone development. It is essential, and that is the point: restriction appears to promote a healthy stress-response that can confer adaptive resilience to senescence.  Other researchers have postulated that methionine restriction causes an increase in autophagy, the process whereby cells break down and recycle unused or damaged cell components. Instead of the free radical theory of aging, this theory would postulate that Methionine restriction induces a starvation-type response where cells begin to recycle their constituents at an increased pace. In this theory, "stress" is a good state to be in, because it puts cells in an active phase of self-repair. Cite: 1 and 2.

* The two other most promising age-defying compounds are rapamyacin (an antibiotic with a plethora of strange and powerful effects throughout the body) and resveratrol.