Investigators at the Riken Institute have demonstrated that while tyrosine is a nonessential amino acid, meaning that it can be synthesized by the body and does not need to be taken up in the diet, it has an essential function as far as nutrient sensing is concerned.

The team reported their results in the July 25, 2022, online issue of Nature Metabolism.

Senior author Fumiaki Obata called the results "totally unexpected."

Obata is a team leader in the Laboratory for Nutritional Biology at the RIKEN Center for Biosystems Dynamics Research.

In order regulate their growth to adapt to changing environmental conditions, it is critical for cells to be able to sense whether they are in an environment of plenty or whether it's belt-tightening time. The mammalian target of rapamycin (mTOR) plays a key role in sensing nutrient availability and orchestrating metabolic decisions accordingly, as does the transcription factor ATF4.

Michael Hall, who received the 2017 Albert Lasker Basic Medical Research Award for his discovery of mTOR, has called mTOR "the brain of the cell." As part of two distinct complexes, mTOR also plays an important role in the relationship between dietary restriction and lifespan extension.

As far as the specific amino acids, much of the attention has gone to two essential amino acids -- methionine and leucine.

Essential amino acids must be taken up in the diet, as the body lacks anabolic pathways to synthesize them. The idea that the best gauge of external nutrient status would be one that the body cannot synthesize on its own makes intuitive sense. And two essential amino acids, leucine and methionine, play important roles in nutrient sensing. Leucine is a predominant regulator of mTORC1, and methionine is critical for translation initiation.

But "somewhat surprisingly, we still do not know why," Obata told BioWorld Science.

Also, much of the work on nutrient sensing has been done in vitro, and there are knowledge gaps with respect to how such signaling works in vivo.

In their work, the team first showed that a low-protein diet in fruit flies activated ATF4. When they added high levels of specific amino acids back into the diet, they found that tyrosine and its precursor phenylalanine prevented ATF4 activation, identifying tyrosine as the critical amino acid whose levels ATF4 was monitoring.

Obata said that why tyrosine would be the critical amino acid is not yet clear, but the amino acid has several characteristics that make it a key metabolic building block.

For one thing, he said, "it is an important precursor for neurotransmitters such as dopamine," and from there, epinephrine and norepinephrine. The route from tyrosine to dopamine goes via L-dopa, which is important for melanization of the skin.

And while research on nutrient sensing has predominantly focused on what happens when nutrient levels are low, for tyrosine, high levels can also be a problem, as it has the lowest solubility among 20 amino acids and can crystallize if present in excess.

Tyrosine also "is [the] only nonessential amino acid that demands amino acid phenylalanine," Obata said. "Other nonessentials are synthesized through central carbon metabolism."

Not just adaptation

If tyrosine is the new kid on the block, leucine is a stalwart in nutrient sensing. A separate study by researchers from Harvard Medical School and Massachusetts Institute of Technology published last week looked at leucine in fruit flies, and also gained some unexpected insights into its role.

In the July 20, 2022, online issue of Nature, the researchers reported on the in vivo role of sestrins, a group of proteins that mediates the effects of leucine on mTOR. The team showed that in addition to its known roles, sestrin also appeared to play a role in enabling Drosophila larvae to sense whether an environment was high in leucine and thus conducive to growth. Sestrin knockout flies were not able to tell when an environment lacked leucine, and consequently did not prefer high-leucine foods. Nor did they preferentially lay eggs on leucine-containing food, which hampered the growth of their larvae.

The authors concluded that "nutrient sensing by mTORC1 is necessary for flies not only to adapt to, but also to detect, a diet deficient in an essential nutrient."