Harnessing the yeast Saccharomyces cerevisiae for the production of fungal secondary metabolites

Abstract

Fungal secondary metabolites (FSMs) represent a remarkable array of bioactive compounds, with potential applications as pharmaceuticals, nutraceuticals, and agrochemicals. However, these molecules are typically produced only in limited amounts by their native hosts. The native organisms may also be difficult to cultivate and genetically engineer, and some can produce undesirable toxic side-products. Alternatively, recombinant production of fungal bioactives can be engineered into industrial cell factories, such as aspergilli or yeasts, which are well amenable for large-scale manufacturing in submerged fermentations. In this review, we summarize the development of baker’s yeast Saccharomyces cerevisiae to produce compounds derived from filamentous fungi and mushrooms. These compounds mainly include polyketides, terpenoids, and amino acid derivatives. We also describe how native biosynthetic pathways can be combined or expanded to produce novel derivatives and new-to-nature compounds. We describe some new approaches for cell factory engineering, such as genome-scale engineering, biosensor-based high-throughput screening, and machine learning, and how these tools have been applied for S. cerevisiae strain improvement. Finally, we prospect the challenges and solutions in further development of yeast cell factories to more efficiently produce FSMs.

Intelligent host engineering for metabolic flux optimisation in biotechnology

“…However, typically if the product is not directly growth-associated (e.g. as with 'secondary' metabolites in idiophase [10,524]) or with two-stage fed-batch regimes where a growth phase is followed by a production phase, one is wanting cells not to grow at the expense of making product [525,526]. Certainly, 'dormant' (non-replicating) cells can be quite active metabolically [527][528][529][530].…”

“…Since both circumstances ultimately seek to maximise the flux to the product of interest, we shall discuss them both, albeit mostly at a high level. Recognising that many pathways are poorly expressed in their natural hosts we shall be somewhat organism-agnostic [ 9 , 10 ], (though we largely ignore cell-free systems) since we are more interested in the principles (whether microscopic [ 11 ] or macroscopic [ 12 ]) than the minutiae.…”

The cell wall and the response and tolerance to stresses of biotechnological relevance in yeasts

“…Since early in human civilization, it has been extensively used in the production of fermented food and beverages, which nowadays include bread, chocolate, wine, beer, cider, sake, spirits (rum, vodka, whisky, brandy), and other alcoholic beverages arising from the fermentation of fruits, honey, and tea ( Walker and Stewart, 2016 ; Parapouli et al, 2020 ). Nowadays, many enzymes, pharmaceuticals, nutraceuticals, and other added-value bioproducts can be produced in engineered yeast cell factories ( Borodina and Nielsen, 2014 ; Runguphan and Keasling, 2014 ; Kwak and Jin, 2017 ; Nielsen, 2019 ; Fathi et al, 2021 ; Wang et al, 2021 ; Arnesen et al, 2022 ; Stovicek et al, 2022 ). The implementation of a sustainable circular bioeconomy requires the development of Advanced Yeast Biorefineries to produce biofuels (e.g., bioethanol and biodiesel), chemicals, materials, and other bioproducts from organic residues from agriculture, forestry, and industry residues ( Madhavan et al, 2017 ; Mukherjee et al, 2017 ; Yamakawa et al, 2018 ; Panahi et al, 2019 ; Saini and Sharma, 2021 ; Usmani et al, 2021 ; Raj et al, 2022 ).…”

Evaluating proteome allocation ofSaccharomyces cerevisiaephenotypes with resource balance analysis

“…A prime example is its use in producing bioethanol 5 for which global demand was 28.91 billion gallons in 2019 6 . S. cerevisiae has also been extensively re-engineered by metabolic engineering to produce various compounds such as fatty acid derivatives and biofuels 7 , building block organic acids 8 , biopharmaceutical proteins 9 , natural products 10,11 , and food additives 12 . For example, industrial-scale production of the antimalarial drug artemisinin’s precursors has been achieved using yeast strain with heterologous expression of Artemisia annua ’s enzymes 13 .…”