It took several years, but a research team has finally succeeded in mapping out the complex metabolism of yeast cells. The breakthrough, recently published in an article in Nature Communications, means a huge step forward in the potential to more efficiently produce protein therapies for diseases such as cancer.

The market for pharmaceuticals that mimic the body's own proteins - protein-based therapeutics - is exploding. Some of them are relatively simple to manufacture in yeast-based cell factories. Insulin and HPV vaccine are two examples that are already under production, but other therapies, such as antibodies to various forms of cancer, are significantly more difficult to manufacture.

"They are currently produced using a cell factory based on a single cell from a Chinese hamster. It's an extremely expensive process. If we can get yeast cells to do the same thing, it will be significantly cheaper - perhaps 10% of what it costs today. Our vision is to eventually be able to mass-produce and supply the entire world with therapies that are too expensive for many countries today," says the senior author.

The protein production of yeast cells comprises more than 100 different processes in which proteins are modified and transported out of the cell. Around 200 enzymes are involved, which makes it a very complex system to engineer. In order to optimize protein production, it is necessary to chart how these 200 enzymes function and work. In the study, this has been done by altering the genetic set of certain key genes, using advanced screening methods in combination with modern genome sequencing techniques.

Protein secretion involves numerous intracellular processes with many underlying mechanisms still remaining unclear. Authors use RNA-seq to study the genome-wide transcriptional response to protein secretion in mutant yeast strains.

They find that many cellular processes have to be attuned to support efficient protein secretion. In particular, altered energy metabolism resulting in reduced respiration and increased fermentation, as well as balancing of amino-acid biosynthesis and reduced thiamine biosynthesis seem to be particularly important.

Authors confirm our findings by inverse engineering and physiological characterization and show that by tuning metabolism cells are able to efficiently secrete recombinant proteins. These findings provide increased understanding of which cellular regulations and pathways are associated with efficient protein secretion.

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