Disruptions in cellular homeostasis and proteostasis are central to many human diseases, yet direct mechanistic investigation in human systems remains constrained by biological complexity and ethical limitations. Therefore, researchers have turned to the use of model systems that allow the more efficient dissection of fundamental cellular processes. The unicellular yeast Saccharomyces cerevisiae has emerged as a powerful eukaryotic model for studying disorders driven by defects in homeostasis and proteostasis. The relevant processes are highly conserved in yeast, enabling precise genetic manipulation and real-time analysis of mechanisms that are difficult to study in mammalian systems. Yeast models have been deployed to study prion propagation, lysosomal enzyme trafficking, and mitochondrial dysfunction. Yeast also provides a versatile platform for drug discovery, particularly through the use of the yeast two-hybrid system and high-throughput screens. Despite an inability to recapitulate the full complexity of multicellular organisms, yeast remains an invaluable tool for investigating human diseases and for the development of therapeutics. This review highlights how yeast has uniquely advanced the understanding of human diseases including those associated with prions, lysosomal proteins, and mitochondria and can be combined with the utility of yeast in drug discovery-collectively establishing yeast as a model for studying human disorders.
The large-scale cultivation of microalgae for aquaculture feed, biofuels, and high value bioproducts is often limited by microbial contamination. While bacteria have long been recognized as major algal symbionts, yeasts, though typically less abundant, are emerging as functionally significant members of the phycosphere. Yeast physiological versatility, stress tolerance, and production of bioactive metabolites enable them to exert disproportionate ecological and biotechnological influence relative to their abundance. Yeasts contribute to algal systems through metabolic complementarity, enhancing nutrient cycling, stress resilience, and culture stability. Several yeast species secrete auxins such as indole-3-acetic acid, stimulating algal cell division and photosynthetic efficiency. Biosurfactants that suppress microbial contaminants, prevent biofilm formation, and stabilize algal cultures are also produced by several yeast species. In co-cultivation systems, yeast-microalgae interactions enhance biomass, lipids, and pigment yields whilst enabling efficient use of waste substrates. Moreover, yeasts associated with microalgae are valuable producers of compounds of biotechnological relevance such as lipids, biosurfactants, pigments, enzymes, and other proteins. This review synthesizes current knowledge on yeast-microalgae associations, emphasizing their ecological relevance, functional versatility, and underexplored potential in sustainable bioprocesses and circular bioeconomy. Highlighting yeasts within algal microbiomes provides new insight into cross-kingdom cooperation and tools for developing resilient, high-performance cultivation systems.
Unravelling the genomic blueprint of a reference laboratory strain of the yeast Saccharomyces cerevisiae 30 years ago opened a new era in understanding yeast biology. Since then, genomics has transformed our ability to study, adapt, improve, and tailor wine yeast strains in the laboratory and manage them in the cellar. This minireview highlights key advances in wine yeast genomics, from early whole-genome sequencing of industrial S. cerevisiae strains to the recent assembly of complex non-Saccharomyces genomes, including the wine spoilage yeast Brettanomyces bruxellensis. Comparative genomics has revealed the genetic foundations of strain specific traits critical to fermentation performance, aroma production, stress tolerance, and microbial interactions in the vineyard and winery. Beyond cataloguing gene content, integrative genomic approaches have elucidated evolutionary dynamics, domestication events, and adaptation to industrial environments. These insights underpin the rational development of novel starter cultures and biotechnological interventions, fostering consistent wine quality and diversity of sensory profiles for targeted consumer markets. Looking ahead, advances in pan-genomics and functional genomics promise to deepen our understanding of metabolic networks, gene-environment interactions, and the broader ecological context of wine fermentation. Collectively, the study of wine yeast genomics not only illuminates fundamental biological principles but also provides practical tools for innovation, including pathway engineering with synthetic enzyme fusions, and the creation of purpose-built synthetic neo-chromosomes. Excitingly, S. cerevisiae, the first eukaryote to have its genome sequenced, is now poised to become the first eukaryote with an entirely synthetic genome ̶ the Sc2.0 project ̶ heralding a bold future for yeast genomics.
Metabolism underpins cellular function by supplying energy, biosynthetic precursors, and redox balance and in yeast there are thousands of metabolic reactions that are tightly coordinated through multilayered regulation. The yeast Saccharomyces cerevisiae has become a central model for studying metabolism and its regulation and following publication of its genome in 1996, this yeast became pivotal in systems biology. Systems biology integrates experimental data with mathematical modeling to analyse complex cellular networks. A major advance for metabolic analysis was the development of flux balance analysis and genome sequencing enabled reconstruction of the first genome-scale metabolic model (GEM) for yeast. This initial GEM described how hundreds of genes, reactions, and metabolites interact across compartments. Subsequent models, including Yeast8 and Yeast9, expanded the coverage and predictive power, and these models enable metabolic comparison, physiological analysis, omics integration, and design of strains that can be used for production of chemicals and biopharmaceuticals. Overall, S. cerevisiae remains a cornerstone of systems biology and biotechnology, with continued advances expected in integrative modeling and engineering applications.
Yeast biodiversity has been extensively investigated by wealthy countries of the Northern Hemisphere. In contrast, despite the widespread use of fermentation practices in the Southern Hemisphere, yeast diversity in this region remains largely underexplored. However, this trend is beginning to shift as several reports have started to document yeast populations both in the natural environment and in association with the fermentation of various substrates, including grape and apple juice, cocoa and coffee beans, grains, fruits, or tree sap. Numerous yeast species from the Southern Hemisphere have now been described and characterized, with whole-genome sequencing providing essential insights into the evolutionary history of wild yeast isolates from this region. This review highlights the emerging research on yeast biodiversity in the Southern Hemisphere and explores the application of diverse yeast species in the food and beverage industries.
Optogenetics is an empowering technology that uses light-responsive proteins to control biological processes. Because of its genetic tractability, abundance of genetic tools, and robust culturing conditions, Saccharomyces cerevisiae has served for many years as an ideal platform in which to study, develop, and apply a wide range of optogenetic systems. In many instances, yeast has been used as a steppingstone in which to characterize and optimize optogenetic tools to later be deployed in higher eukaryotes. More recently, however, optogenetic tools have been developed and deployed in yeast specifically for biotechnological applications, including in nonconventional yeasts. In this review, we summarize various optogenetic systems responding to different wavelengths of light that have been demonstrated in diverse yeast species. We then describe various applications of these optogenetic tools in yeast, particularly in metabolic engineering and recombinant protein production. Finally, we discuss emerging applications in yeast cybergenetics-the interfacing of yeast and computers for closed-loop controls of yeast bioprocesses-and the potential impact of optogenetics in other future biotechnological applications.
The human gastrointestinal (GI) microbiota has come to be recognized as a modulator of health. However, interest in fungi and their function as members of the microbiota has lagged behind interest in bacteria. Despite the lack of historical interest, fungi are prevalent in the human GI tract and have an outsized impact on host immunity. In this review, we aim to examine the associations and potential impact of yeasts on human health outcomes. This review summarizes the associations between yeasts and inflammatory bowel diseases, highlights the predictive service that yeasts may provide in cancer therapy, and explores the possibility of yeasts as therapeutic effectors. There remain significant challenges in data analysis and identifying the relevance of fungal morphology; however, the pathways for clinical translation open to yeasts in the GI tract make these challenges worth overcoming.
Whisky is an alcoholic beverage derived from fermented grain mash that is distilled into 'new make spirit' before maturing in barrels. While most research on whisky innovation has focused on raw materials or maturation, yeast strain selection remains a relatively underexplored avenue for product diversification. Here, we evaluated yeast diversity for whisky production by screening 110 strains sourced from Canadian vineyards for maltose utilization followed by assessing 29 candidate strains in malt extract fermentations. Seven strains representing distinct genetic backgrounds were advanced to pilot-scale fermentations, including a commercial whisky control strain of Saccharomyces cerevisiae, four other S. cerevisiae strains, one Torulaspora delbrueckii strain, and one Saccharomyces uvarum strain isolated from British Columbia wine fermentations. Fermentation performance was assessed via high performance liquid chromatography, and volatile organic compounds in new make spirits were profiled using headspace solid-phase microextraction-gas chromatography-mass spectrometry. All strains completed fermentation except T. delbrueckii, despite undergoing sequential inoculation with a commercial whisky strain. Fermentations with non-S. cerevisiae yeast strains contained elevated levels of glycerol and organic acids. Volatile organic compounds analysis identified 43 compounds, revealing strain-dependent aroma diversity. Notably, S. uvarum P01E08 was enriched in 2-phenylethyl octanoate, phenylethyl alcohol, and phenylethyl acetate. These findings highlight diverse regional yeast selection as a viable strategy to expand whisky sensory diversity.
Completion of the Saccharomyces cerevisiae genome sequence three decades ago marked a defining moment in eukaryotic genomics. Beyond a technical milestone, it established a shared reference that transformed how yeast biology is studied, interpreted, and extended across disciplines. This Editorial revisits the yeast genome sequencing project with a focus on the scientific culture that enabled it: an extraordinarily collaborative community willing to coordinate effort, share resources, and collectively tackle biological complexity. That consilient culture proved essential in converting a static DNA sequence into a dynamic framework for discovery, enabling systematic exploration of gene function, cellular organization, and genome-scale biology. As this Special Collection celebrates the 30th anniversary of the yeast genome sequence, we reflect on how shared infrastructure, and collective ambition turned the genome sequences of three related lab strains (S288c and its derivatives FY1679 and AB972) into a lasting platform for innovation. Apart from enabling the field of population genomics and access to the vast genetic diversity of the species, these foundations have facilitated the synthesis and assembly of all 16 chromosomes of the same laboratory strain of S. cerevisiae, bringing the Sc2.0 project within reach of creating the first eukaryotic cell with a fully synthetic genome. This transition-from genome reading to genome writing-positions yeasts as powerful systems for iterative design-build-test-learn cycles and for reimagining genomes of other Saccharomyces and non-Saccharomyces strains (including those used in industry) as highly modifiable biological platforms.
Cyclic disulfide-rich peptides have become increasingly popular in drug development because their structures enhance molecular stability and allow for mutagenesis to introduce non-native functions. This review focuses on yeast-based platform technologies and their utility in advancing cyclic disulfide-rich peptides as drug modalities and for large-scale biomanufacturing. These technologies include yeast surface display which facilitates the screening of large libraries to develop peptide binders with strong affinity and selectivity for protein targets, while maintaining the innate high stability of the peptide scaffold via protease-based selection pressure. We also describe a recently developed platform that leverages yeast's ability to secrete correctly folded disulfide-rich peptides while simultaneously displaying peptide or protein tags on their surfaces. In combination with microfluidics technology, the platform creates single-cell yeast-in-droplets reactors, enabling the screening of large libraries based on functional output rather than solely on binding affinity. After identifying cyclic peptide candidates through library-based discovery, these candidates can be produced using a versatile yeast-based bioproduction platform. Traditionally, cyclic disulfide-rich peptides are produced through solid-phase synthesis, a method that generates significant amounts of toxic waste. In contrast, yeast-based bioproduction offers an environmentally sustainable alternative. It has the capability to produce structurally distinct peptides with minimal adjustments and is easily scalable using microbial fermenters, making it an ideal choice for large-scale production.
Yeast biodiversity and machine learning (ML) are transforming the landscape of metabolic engineering. While Saccharomyces cerevisiae remains foundational to industrial biotechnology due to its genetic tractability and robust growth, it struggles to synthesize complex metabolites, utilize alternative feedstocks, and withstand industrial stresses. Non-conventional yeasts such as Yarrowia lipolytica and Ogataea polymorpha possess traits such as thermotolerance, acid resistance, and lipid accumulation, making them promising alternatives. However, broader adoption remains limited by insufficient genetic tools and low predictability of engineered components across species. Recent ML advances are addressing these gaps by enabling accurate prediction of genetic part function, optimizing gene expression, and discovering novel biosynthetic components in diverse yeasts. These tools support rational selection of genetic elements and pathway configurations tailored to non-model hosts, streamlining the design-build-test-learn cycle. Leveraging biodiversity expands the available yeast chassis and toolkits, improving strain robustness under industrial conditions. This mini-review discusses how yeast biodiversity is being harnessed to broaden engineering strategies and highlights recent ML advances driving data-guided strain and pathway design. Special attention is given to ML-guided identification and optimization of genetic elements. Together, evolutionary diversity and intelligent computation promise more modular, predictive, and scalable yeast platforms for next-generation metabolic engineering.
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This article explains the biochemical basis of the synergistic effect of oxythiamine (OT) and ketoconazole (KTC) against Malassezia pachydermatis yeast, which was isolated from dogs exhibiting clinical signs of otitis externa. All strains were incubated on MLNA medium supplemented with OT, KTC, or a mixture of both compounds. We found that the ergosterol content was reduced by the compounds tested, both separately (20%-50%) and in combination (80%). OT alone and in combination with KTC reduced NADPH levels. However, we found no differences in acetyl-CoA levels under the influence of the compounds tested. We suggest that the synergism of OT and KTC is due to a reduction in the rate of the mevalonate pathway by inhibition of NADPH influx from the pentose phosphate pathway (transketolase inhibition by OT) and inhibition of C14-α-lanosterol demethylase by KTC. The proposed mechanism may be versatile for other yeast-like species, making the combination of OT and KTC a promising treatment option for superficial, opportunistic yeast-like infections.
The yeast Saccharomyces cerevisiae converts amino acids into volatile compounds with fruity and floral aromas during fermentation. These amino acid-derived aroma compounds play a critical role in defining the taste and flavor of alcoholic beverages such as sake, beer, and wine. The productivity of amino acid-derived aroma compounds depends on the intracellular availability of their precursor amino acids. Therefore, breeding yeast strains that accumulate amino acids provides a practical approach to developing alcoholic beverages with more unique and attractive sensory characteristics. In this minireview, we describe the isolation of yeast strains that overproduce branched-chain amino acids and phenylalanine, obtained through conventional mutagenesis of industrial brewing yeasts. We also discuss the mechanisms responsible for the increased production of these amino acids in the mutant strains, including altered feedback regulation and transcriptional control of key enzymes involved in their biosynthesis. In addition, we briefly introduce a plasmid-free genome editing system that enables precise modification of metabolic pathways without the integration of foreign DNA, allowing the construction of strains that are not classified as genetically modified organisms. This method represents a promising tool that allows flexible and fine-tuned engineering of yeast metabolic pathways, including the development of strains with tailored aroma profiles.
Non-conventional yeasts are recognized as valuable hosts for producing biofuels, pharmaceuticals, and other high-value chemicals, owing to their diverse physiological traits, ability to utilize various substrates, and greater tolerance to environmental stresses compared to conventional model yeast Saccharomyces cerevisiae. To fully optimizing metabolic flux toward desired products, effective genetic engineering tools enabling precise modulation of gene expression and coordinated control of metabolic pathways are essential. In this context, we discussed classical transcriptional regulation tools like promoters, and transcription factors, alongside innovations in synthetic biology that allow metabolic engineering in non-conventional yeasts to produce higher biofuels and other useful products, promoting the development of sustainable resources, and assisting the development of innovative bio-products. It also discussed innovative programmable technologies, such as CRISPR/Cas-mediated transcriptional activation and repression, as well as dynamic regulatory systems that can fine-tune metabolic routes and balance cellular resources. Strategies for promoter engineering, transcription factor manipulation for transcriptional regulation, and metabolic rewiring were highlight as methods to boost pathway efficiency and yields. This review concluded with current challenges and future directions, focusing on integrating synthetic biology and systems biology to create robust, controllable transcriptional frameworks for next-generation yeast cell factories.
Yeast shares a longer than 10 000-year history with humans in food fermentation by producing various volatile flavor compounds that contribute to the final taste and aroma of foods. Yeast-associated volatile flavor compounds include esters, benzenoids, sulfur compounds, and phenolic derivatives, which enhance the sensory complexity of fermented foods and beverages. Genome-scale technologies have advanced and transformed our understanding of the genetic and evolutionary drivers of volatile flavor diversity. The conventional approach to aroma enrichment and flavor balancing through single-strain optimization has been redefined through yeast cofermentation strategies, such as the pairing of Saccharomyces cerevisiae with nonconventional yeast species. This minireview summarizes the latest genomic insights into volatile flavor compound formation through ester, benzenoid, sulfur, and phenolic pathways in various yeast species and highlights the shaping of the next generation of food fermentation innovation via cofermentation combined with omics analysis, followed by a future perspective on synthetic biology for industrial applicability.
The yeast Saccharomyces cerevisiae coordinates growth, metabolism, and stress adaptation through signaling pathways that respond to changes in nutrient availability. Classical nutrient-sensing systems, including the cAMP-protein kinase A (PKA), Snf1/AMP-activated protein kinase, target of rapamycin complex 1 (TORC1)-Sch9, Ssy1-Ptr3-Ssy5, and general amino acid control pathways, have revealed how yeast senses and responds to extracellular carbon, nitrogen, phosphate, and amino acid levels. In addition to these established pathways, plasma-membrane nutrient transporters also function in signaling rather than solely mediating substrate uptake. These dual-function proteins, termed nutrient transceptors, couple nutrient transport or extracellular nutrient recognition to rapid intracellular responses, often activating PKA without detectable changes in cAMP levels. This review focuses on yeast nutrient transceptors, specifically Gap1, Mep2, Pho84, Sul1/Sul2, Can1, Ftr1, and Zrt1. These proteins link extracellular nutrient availability to intracellular regulatory responses, including trehalose mobilization, stress resistance, growth resumption, filamentous development, and, in some cases, TORC1-Sch9 signaling. Mechanistic insights, including transport-signaling uncoupling and potential physical association with downstream protein kinases, are also discussed. Collectively, this evidence establishes nutrient transceptors as an essential additional layer of nutrient sensing in yeast, highlighting their role in translating extracellular nutrient cues into cellular responses.
High-throughput yeast engineering is being transformed by biofoundries that integrate automation, artificial intelligence (AI), and standardized workflows. This review examines how these facilities accelerate strain development through the Design-Build-Test-Learn (DBTL) cycle, with advances in genome editing, phenotypic screening, and predictive modelling. It highlights Australia's involvement through the Australian Genome Foundry, Idea-BIO, and the CSIRO Biofoundiry and explores global efforts to overcome reproducibility and standardization challenges. Despite progress, key barriers remain, including protocol variability and integration of AI tools. We also highlight the opportunity for a shift toward autonomous, self-optimizing 'self-driving labs' that transition from DBTL to Design-Build-Deploy cycles. The future of yeast engineering depends not only on technological innovation, but also on the harmonization of international standards, data governance, and ethical safeguards. If fully realized, the convergence of robotics, AI, and synthetic biology will redefine yeast engineering, leading to step changes in strain performance for a variety of important products, thus enabling economic and sustainable biomanufacturing at scale.
Aromatic compounds are a diverse group of bioactive molecules with broad applications in the polymer, food, feed, cosmetic, and pharmaceutical industries. To address climate change and the depletion of fossil resources, there is growing interest in their sustainable production. Yeast cell factories offer an attractive alternative to conventional chemical synthesis by converting aromatic amino acids (AAAs) into a broad range of valuable aromatic products. Among AAAs, L-tryptophan (Trp) is distinguished by its indole moiety and serves as a key precursor for numerous high-value natural products. This review summarises recent advances in the engineering of yeast to produce tryptophan-derived compounds. Furthermore, it discusses current metabolic engineering strategies, synthetic biology tools, and the remaining challenges that must be overcome to achieve efficient, scalable, and economically viable biosynthesis of tryptophan-derived aromatic compounds in yeast.
Rhodotorula toruloides is an oleaginous yeast with great potential for chemical and biofuel production, due to its ability to utilize lignocellulosic biomass and to produce high levels of carotenoids and storage lipids. However, its broader application in biotechnology has been limited by the lack of efficient genetic transformation methods. Although protoplast transformation is wildly used in fungal systems, it has remained largely unexplored in R. toruloides. In this study, we established a protoplast transformation protocol using linear DNA fragments and R. toruloides strain BOT-A2, a recently isolated strain with high lipid-producing potential. We first confirmed that BOT-A2 is a MAT A2 haploid strain. We then produced a β-1,3-glucomannanase (Man5C) that effectively digests the R. toruloides cell wall. Key parameters affecting transformation efficiency were systematically optimized, including the Man5C digestion conditions, antibiotic selection pressure, cell growth phase, protoplast yield and viability, PEG formulation, calcium ion concentration, and regeneration conditions. Using the optimized protocol, we successfully transformed BOT-A2 with three heterologous resistance cassettes (hygromycin R, bleomycin, and G418) yielding 190, 226, and 244 transformants per µg of DNA, respectively. This method provides a platform for genetic manipulation and is expected to facilitate both fundamental research and metabolic engineering in R. toruloides BOT-A2.