As the Earth’s population grows and people are expected to live longer in the future, better and more reliable therapies to treat human diseases such as Alzheimer’s and cardiovascular diseases are crucial.

To cope with the challenge of ensuring healthy aging, a group of international scientists investigated the potential of biosynthesizing several polyamines and polyamines analogues with already known functionalities in treating and preventing age-related diseases. They published their study (“Engineering yeast metabolism for the discovery and production of polyamines and polyamine analogues”) in Nature Catalysis.

“Structurally complex and diverse polyamines and polyamine analogues are potential therapeutics and agrochemicals that can address grand societal challenges, for example, healthy aging and sustainable food production. However, their structural complexity and low abundance in nature hampers either bulk chemical synthesis or extraction from natural resources,” write the investigators.

“Here we reprogrammed the metabolism of baker’s yeast Saccharomyces cerevisiae and recruited nature’s diverse reservoir of biochemical tools to enable a complete biosynthesis of multiple polyamines and polyamine analogues. Specifically, we adopted a systematic engineering strategy to enable gram-per-liter-scale titers of spermidine, a central metabolite in polyamine metabolism. To demonstrate the potential of our polyamine platform, various polyamine synthases and ATP-dependent amide-bond-forming systems were introduced for the biosynthesis of natural and unnatural polyamine analogues.

The yeast platform serves as a resource to accelerate the discovery and production of polyamines and polyamine analogues, and thereby unlocks this chemical space for further pharmacological and insecticidal studies.”

One of the most interesting molecules to study is spermidine, which is a natural product already present in people’s blood and an inducer of autophagy. i.e., an essential cellular process for clearing damaged proteins, such as misfolded proteins in brain cells that can cause Alzheimer’s. When people get older the level of spermidine in the blood decrease and dietary supplements, or certain food products are needed to maintain a stable and high level of spermidine in the blood.

However, those products are difficult to produce with traditional chemistry due to their structural complexity and extraction of natural resources is neither a commercially viable nor a sustainable approach.

Therefore, the researchers instead decided to use classical metabolic engineering strategies to engineer the yeast metabolism to produce polyamines and polyamines analogues.

“This group of molecules has huge potential in addressing important societal challenges and it seemed logical to try and produce them with the help of biology,” emphasizes Jiufu Qin, PhD, senior researcher at The Novo Nordisk Foundation Center for Biosustainability, DTU.

Solid vantage point

The team of scientists explored seven biosynthetic routes that synthesizes spermidine from arginine or ornithine and by employing flux balance analysis they could estimate the maximum theoretical yield of each pathway.

After establishing the most efficient pathway for spermidine and systematically engineering the cellular metabolism of yeast they managed to ultimately reach a production of spermidine at titers 2.3 gram per liter on lab scale. An initial result that proves the potential of utilizing nature’s large and diverse reservoir of biochemical tools to push forward products that can meet the challenges of population aging and a lack of sufficient food supplies.

“We expect that our studies lay the groundwork for fermentation-based manufacture of diverse polyamines and polyamine analogues to further unlock this field’s potential for pharmacological and agricultural applications, “says Jens Nielsen, PhD, professor at Chalmers University of Technology and CEO at BioInnovation Institute.

But low enzyme activity causing feedback regulation and thereby compromising the product yield still needs to be overcome.

Even though the strain might need to be improved further, scale-up towards commercial production is already ongoing since the current titers are deemed sufficient for initializing production.

The company Chrysea Labs has been established based on this scientific study and the company has a mission of developing healthy lifespan nutritional interventions by ameliorating the natural occurring anti-aging mechanism autophagy that recycle the cellular process, which is critical for maintaining cell health, renewal and survival.

Since the market is expected to grow in the coming years and only a few competitors are currently present in the field, Chrysea Labs hopes to be a key player in ensuring healthy aging.

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