Antioxidant Compound, with Aid of Baker’s Yeast, May Offer Oral Supplement to Offset Alzheimer’s

A natural compound with antioxidative properties that might help to delay the onset of neurodegenerative diseases like Alzheimer’s can now be produced in baker’s yeast, a study reports.

This new way of producing ergothioneine, as the compound is known, may lead to a commercially viable new treatment for people with a range of neurodegenerative diseases.

The study, “Engineering the Yeast Saccharomyces cerevisiae for the Production of L-(+)-Ergothioneine,” was published in the journal Frontiers in Bioengineering and Biotechnology.

Ergothioneine (ERG) is an unusual but naturally occurring antioxidant that can ease or prevent the cellular stress associated with neurodegenerative diseases. People cannot naturally produce ERG, but acquire it from their diet. This compound is mainly produced by enzymes in bacteria and fungi, and plants are thought to take from the soil ERG excreted by fungi.

Previous studies have shown that individuals with certain neurodegenerative diseases have significantly lower blood levels of ERG than others. Studies in animal models also suggest that ERG might prevent the onset of diseases such as Alzheimer’s and dementia.

Alzheimer’s patients could potentially benefit by taking ERG as a dietary supplement, much as people do with vitamins.

“Because of the beneficial effects and possible involvement of ERG in disease, ergothioneine may potentially prove its value in the global dietary supplement market, which was estimated at some $241.1 billion in 2019. Currently, commercial ergothioneine is extracted from mushrooms or synthesized chemically,” the researchers wrote.

Ergothioneine is complex and expensive to produce using chemical synthesis. But its production “in microbial cell factories would provide a sustainable low-cost alternative to its current manufacturing processes,” they added.

Researchers at the Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain) in Denmark developed a cost-effective and relatively easier way to potentially produce viable amounts of ERG.

They started by screening enzymes from bacteria (M. smegmatis) and different fungi (C. purpurea, N. crassa, S. pombe) in numerous combinations, to identify those that yield the highest ERG production.

Once they discovered that two specific fungal enzymes, NcEgt1 and CpEgt2, made the best combination with regard to producing higher amounts of ERG, they inserted these enzymes into a host — specifically, baker’s yeast (S. cerevisiae).

The fungal pathway for ERG production only uses two enzymes, compared to five for a bacterial pathway. The fungal ERG pathway also doesn’t use energy to the extent that bacteria do, making it a more efficient biosynthesis pathway with a better product yield.

“The bacterial pathway in E. coli uses a lot of energy while the fungal pathway in yeast doesn’t. That could lead to a production benefit. Also, yeast is a safe and well-known production host for food supplements,” Steven van der Hoek, the study’s first author, said in a press release.

When researchers supplemented a media (the liquid that contains all the necessary growth factors for yeast cells to grow) with amino acids — the building blocks of proteins — that are incorporated into ERG, they were able to significantly increase ergothioneine production.

Adding the amino acids to this media — working as fermentation process of sorts — helped increase ERG production to 0.6 g/L in 84 hours, the study reported. In comparison, the current best ERG production using E. coli bacteria was 1.3 g/L in 216 hours.

“As the first report of ergothioneine production in S. cerevisiae, our investigation into the impact of amino acid supplementation and the flux in the ERG pathway will help further ERG production efforts by yeast fermentation,” the researchers wrote.

The team is now trying to optimize this technique by continuously engineering the strain, with the goal of creating  a commercially viable product.

Researchers emphasize that ERG’s benefits in disease have so far only been reported in animal models. More studies are essential to understand if ERG as a supplement might help to treat people with or at risk of diseases like Alzheimer’s.