Cells in biological systems often face nutrient limitations and must rewire their metabolic processes to restore a balanced state. Given this, researchers have compared cell metabolism to an economy, capable of managing a metabolite’s supply based on its demand for different processes. Although this idea dates back to early 2000s, how cells prioritise the restoration of different resources — such as amino acids — on supply disruptions remains poorly understood.

Now, bridging this knowledge gap, research led by Sunil Laxman, Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, found that cells faced with nutrient limitation prioritise restoration of amino acids with higher demand and lower supply costs. Their results, published in Nature Communications, provide an economic framework for prioritisation strategies used by cells on facing nutrient limitation. Laxman says,

This work provides insights into resource allocation strategies employed by cells, and informs researchers how to more efficiently metabolically engineer cells.

Vijay Jayaraman from Indian Institute of Science Education and Research (IISER) Thiruvananthapuram, who was not involved in the study, summarises the results metaphorically: The government will prioritise restocking cheaper, but more in-demand vegetables like onions over expensive and less demanded vegetables like beans if their stocks run out. 

To understand prioritisation strategies employed by cells under nutrient starvation, Laxman and team first grew yeast cells in amino acid-rich medium. They then shifted these cells into medium lacking amino acids, which would disrupt external supply, leaving cells to rely on synthesising their own amino acids. Monitoring a transcription factor — Gcn4 — involved in amino acid biosynthesis revealed its higher activity on moving cells into medium without amino acids.

The team wondered whether Gcn4 activity changes when specific amino acids are missing from the medium. They grouped amino acids together depending on their chemical structures and metabolic origins, and shifted yeast cells into medium lacking each of these groups. They observed different Gcn4 activity levels depending on which amino acid group was absent, indicating that cells prioritize restoration responses for different amino acids. 

The researchers next investigated whether the extent of this response depends on the demand and biosynthetic cost of the missing amino acid. There is no established cost-scale for amino acid synthesis, so the team devised one by factoring components like phosphate bonds and metabolic precursors required to supply an amino acid. They further calculated the demand for each amino acid toward both metabolism and protein synthesis. 

They observed that amino acids with the highest demand have low supply costs and vice versa. Moreover, removing the amino acid with the highest demand and lowest cost from the medium invoked the highest response as measured by Gcn4 activity. 

As the results progressed, ​“it got more enlightening,” says Swagata Adhikary, a graduate student and co-first author alongside postdoctoral researcher Ritu Gupta, National Institutes of Health, USA. ​“It was like getting a perspective of cells as the economy,” as pieces of the puzzle started falling into place, Adhikary says. 

“The novelty of the paper resides in the simplistic but profound model where they calculate the demand and supply of each amino acids,” says Jayaraman. However, Laxman notes that their current calculations estimate reasonable values for demand and supply cost, but they are ballpark figures.

Jayaraman further notes that the experimental design of transiently limiting amino acids may not capture the real-life scenario of nutrient deprivation. Nevertheless, the study provides a clear picture about responses to nutrient limitation, which opens up more questions to be answered, Jayaraman adds. 

Laxman concurs. This has gotten us thinking about whether we can study these in more complex systems than yeast, he says. 

I would love to go down that direction.