Why do some yeast cells produce ethanol? Scientists have wondered about this apparent waste of resources for decades. Now, scientists think they have a solution: yeast cells produce ethanol as a 'safety valve', to prevent overload when their metabolic operation reaches a critical level. The implications of this new theory, which was published in Nature Metabolism could be far-reaching, as it also explains why cancer cells waste energy by producing lactate, known as the Warburg effect.

Cells use nutrients like glucose to make new cells. But sometimes, some of these nutrients are wasted. For example, the yeast Saccharomyces cerevisiae, which is used to produce beer, breaks glucose down into ethanol rather than carbon dioxide. 'Metabolizing a six-carbon molecule to a two-carbon molecule, rather than to carbon dioxide, means part of the energy and matter stored in glucose is lost. It makes no sense', says the senior author.

Evolution should have put an end to such a waste of resources, so biologists have tried to find a reason for its existence. 'And similar wastefulness can be seen in other cells', says the senior author. A widely known example is cancer cells. These fast-growing cells excrete lactate, which is a similar waste of energy. And many bacteria waste energy as well. 'This similarity between different organisms made us wonder whether there was a common denominator.'

By adding thermodynamics to a model with around 1,000 chemical reactions and combining the model with experimental data, researchers were able to determine the Gibbs energy dissipation rate as a function of glucose uptake. At first, the Gibbs energy dissipation increases with increasing rates of glucose consumption, but then a plateau is reached - and at that point, ethanol production starts. 'This is the point where the cells switch from respiration to fermentation', explains the senior author.

The team obtained similar results for the gut bacterium E. coli, with a plateau at a comparable level of Gibbs energy dissipation. The senior author says: 'Yeast and E. coli live in completely different environments, yet have about the same dissipation limit that is even at about the same value. This suggests that this limit is something universal.' The exact reason for this limit is still unknown, but the scientists have come up with a working hypothesis. 'Cellular metabolism has a maximum rate at which it can still operate.' When this is reached, the cells open a 'safety valve' and glucose is broken down to ethanol, acetate or lactate, leaving part of the energy unused.

So what is causing this limit? 'Part of the energy is dissipated as heat, but this is too little to bother the cells. Our idea is that when enzymes catalyze a chemical reaction, they get a tiny push during the reaction, which makes them move. If they work very fast, this could mean that there is too much movement inside the cells, which could damage certain cellular structures.' Studies on the movement of enzymes inside the cell at different metabolic rates could confirm this.

Not all cells need a safety valve, though. 'Some yeast strains have a slow glucose uptake, so they will never be in danger of metabolic overload. And indeed, these yeast species don't produce ethanol', says the senior author.

https://www.nature.com/articles/s42255-018-0006-7

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fan-upper-limit-on-gibbs&filter=22