Yeast Cell Factories on the Horizon

by Jens Nielsen (Science Magazine) For thousands of years, yeast has been used for making beer, bread, and wine. In modern times, it has become a commercial workhorse for producing fuels, chemicals, and pharmaceuticals such as insulin, human serum albumin, and vaccines against hepatitis virus and human papillomavirus. Yeast has also been engineered to make chemicals at industrial scale (e.g., succinic acid, lactic acid, resveratrol) and advanced biofuels (e.g., isobutanol) (1). On page 1095 of this issue, Galanie et al. (2) demonstrate that yeast can now be engineered to produce opioids (2), a major class of compounds used for treating severe pain. Their study represents a tour de force in the metabolic engineering of yeast, as it involved the expression of genes for more than 20 enzymatic activities from plants, mammals, bacteria, and yeast itself. It clearly represents a breakthrough advance for making complex natural products in a controlled and sustainable way.

Yeast has previously been recruited for producing complex natural products through the reconstruction of biosynthetic pathways taken from plants or animals (3). This is done by transferring genes that encode enzymes of the metabolic pathway, from the organism that naturally produces the chemical of interest, into yeast. A key requirement is that this heterologous metabolic pathway hooks up to endogenous yeast metabolism. As central metabolism is highly conserved between different organisms, it is generally possible to identify a metabolite in the endogenous yeast metabolism that can be used as a precursor for the heterologous pathway. Indeed, using this approach, yeast was engineered to produce hydrocortisone (a steroid used to synthesize drugs with anti-inflammatory and antiproliferative effects) by recruiting part of the endogenous yeast pathway that generates ergosterol (4). Several endogenous yeast enzymes were put to use, but it was still necessary to express more than 10 mammalian enzymes in combination with overexpressing the yeast genes to enable production of hydrocortisone from glucose. Ergosterol is synthesized via the so-called mevalonate pathway (also used for cholesterol biosynthesis in mammals), and plants use this pathway to make a wide range of isoprenoids (or terpenoids). Members of this family have a broad spectrum of applications, including food products, pharmaceuticals, cosmetics, and biofuels (3), and through recruitment of the mevalonate pathway, it has been possible to engineer yeast to produce compounds normally extracted from plants [such as perfumes (e.g., santalene) (5)]. Several companies are currently working on developing this technology to enable the production of fine chemicals through yeast fermentation, thereby providing a stable, sustainable, and scalable source of the desired compound.

By demonstrating that a 23-step biosynthetic pathway can be reconstructed in yeast, the study advances the ability to ensure sustainable production of fuels, chemicals, and pharmaceuticals. Even though the 2010 market for renewable chemicals was only about 1% of the total chemical market (about $30 billion out of a total market of $3 trillion), metabolic engineering of cell factories, and especially yeast, has clear potential to increase this proportion in the future. READ MORE