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At least 19 recordsLinked to original sources
PubMed2026

A yeast model of 5-oxoproline accumulation reveals a general toleration to 5-oxoproline.

5-oxoproline (5-OP) or pyroglutamic acid is an intermediate in the degradation arc of the glutathione cycle. It is metabolized into glutamate through the action of the 5-oxoprolinase enzyme, the only enzyme known to act on this metabolite. 5-OP has long been known to be relatively inert with a proposed role as an osomoprotectant. Recent studies on the 5-oxoprolinase enzyme in mammalian cells have, however, shown that knockdown or deletion of 5-oxoprolinase makes mice (and humans) prone to heart failure, an effect ascribed to oxidative stress caused by a twofold increase in 5-OP. To examine the consequences of 5-oxoproline accumulation more rigorously, we created a yeast model for 5-oxoproline accumulation. Using this model, we observed retardation of growth only when intracellular levels of 5-OP were increased 12- to 20-fold over normal levels. Performing an analysis of transcriptomic changes under these conditions, we observed a large number of genes were differentially regulated and while there was no unifying dysregulated pathway, there was an upregulation of various efflux pumps. Ultimately, modulating the expression of these genes by knockout or overexpression highlighted that many of the upregulated genes were involved in the cellular response to 5-OP accumulation. However, our results failed to show any significant oxidative stress response. In conclusion, our study suggests a need to reevaluate previous suppositions of the 5-OP induced oxidative stress response and proposes alternate mechanisms for this effect.

Pyrrolidonecarboxylic Acid↗
PubMed1992

Human estrogen receptor regulation in a yeast model system and studies on receptor agonists and antagonists.

An expression system that utilized yeast copper metallothionein promoter and ubiquitin fusion technology to express the human estrogen receptor gene in yeast is described. We have studied the biochemical and transcriptional regulatory properties of the human estrogen receptor. The biochemical properties of the yeast expressed receptors are identical to the receptors isolated from human tissue. Estradiol mediated activation of transcription by the receptor was studied by a reporter beta-galactosidase gene where expression was under the control of estrogen response elements. Using this expression system and a hyperpermeable yeast strain we have studied the effects of various antiestrogens on the regulation of estrogen receptor function. We demonstrate that tamoxifen and ICI 164,384 are capable of binding to the receptor but neither antiestrogen was able to block the estradiol mediated increase in transcription. In fact, both antiestrogens exerted weak agonist activity in this system.

Amino Acid Sequence↗
PubMed2025

Evolution and applications of genome-scale metabolic models in yeast systems biology studies.

Genome-scale metabolic models (GEMs) can be used to simulate the metabolic network of an organism in a systematic and holistic way. Different yeast species, including Saccharomyces cerevisiae, have emerged as powerful cell factories for bioproduction. Recently, with the dedicated efforts from the scientific community, significant progress has been made in the development of yeast GEMs. Numerous versions of yeast GEMs and the derived multiscale models have been released, facilitating integrative omics analysis and rational strain design for different types of yeast cell factories. These advancements reflected the evolution and maturation of yeast GEMs together with a model ecosystem around them. This review will summarize the development and expansion of yeast GEMs and discuss their applications in yeast systems biology studies. It is anticipated that yeast GEMs will continue to play an increasingly important role in pioneering yeast physiological and metabolic studies in coming years.

Systems Biology↗
PubMed1992

Partial rRNA sequences in marine yeasts: a model for identification of marine eukaryotes.

The V3 variable region of the large subunit rRNA was examined for nucleotide sequence signatures as potential taxonomic tools. Data are presented on 117 species, representing 23 genera of basidiomycetous yeasts. The results of nucleotide sequence alignments indicate that strains within species have identical base sequences and that species may differ from one another by one to more than 100 base positions. Phylogenetic analyses of the alignments indicates relationships among species, including the prediction of synonymous species and the clustering of species belonging to the Ustilaginales and Tremellales. These results suggest that species-specific nucleotide sequences can be used for the development of techniques for population analyses of a variety of marine and other microeukaryotes.

Animals↗
PubMed1979

Kinetic modelling of yeast phosphofructokinase.

Phosphofructokinase from baker's yeast (Saccharomyces cerevisiae) is an octameric enzyme which exhibits complex allosteric behaviour. In contrast to mammalian phosphofructokinase, the enzyme does not show association-dissociation behaviour. A systematic kinetic investigation at pH 7.2 in dependence on the substrates, fructose 6-phosphate and ATP as well as on the effectors AMP and ADP is presented. The results are interpreted in terms of a structure oriented theoretical model. Because the two state model of Monod, Wyman and Changeux proved to be insufficient for interpretation of the experimental data, it was extended to a four state model in which the basic conformations R and T of the enzyme are split into subconformations R1 and R2 as well as T1 and T2, respectively. It is assumed that fructose 6-phosphate and the adenine nucleotides influence different allosteric equilibria. The model permits a precise quantitative description of the experimental data.

Adenosine Diphosphate↗
PubMed2026

Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.

Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.

Humans↗
PubMedDate not supplied

Monitoring cell concentration and activity by multiple excitation fluorometry.

Four key cellular metabolic fluorophores--tryptophan, pyridoxine, NAD(P)H, and riboflavin--were monitored on-line by a multiple excitation fluorometric system (MEFS) and a modified SLM 8000C scanning spectrofluorometer in three model yeast fermentation systems--bakers' yeast growing on glucose, Candida utilis growing on ethanol, and Saccharomyces cerevisiae RTY110/pRB58 growing on glucose. The measured fluorescence signals were compared with cell concentration, protein concentration, and cellular activity. The results indicate that the behavior and fluorescence intensity of various fluorophores differ in the various fermentation systems. Tryptophan fluorescence is the best signal for the monitoring of cell concentration in bakers' yeast and C. utilis fermentations. Pyridoxine fluoresce is the best signal for the monitoring of cell concentration in the S. cerevisiae RTY110/pRB58 fermentation. In bakers' yeast fermentations the pyridoxine fluorescence signal can be used to monitor cellular activity. The NAD(P)H fluorescence signal is a good indicator of cellular activity in the C. utilis fermentation. For this fermentation NAD(P)H fluorescence can be used to control ethanol feeding in a fed-batch process.

Candida↗
PubMed2026

CoMR: an integrative scoring pipeline for comprehensive mitochondrial proteome reconstruction across eukaryotes.

Mitochondrial proteome reconstruction from eukaryotic sequence data typically relies on prediction of mitochondrial targeting signals (MTSs). However, MTS predictors are primarily trained on model organisms and may perform poorly in phylogenetically divergent lineages or in organisms with atypical or reduced targeting sequences. Accurate reconstruction therefore requires integration of complementary sources of evidence beyond targeting prediction alone. We developed Comprehensive Mitochondrial Reconstructor (CoMR), an integrative workflow that combines targeting prediction, curated homology searches, large-scale similarity searches, and automated phylogenetic analysis within a unified scoring framework. Benchmarking on the model yeast Saccharomyces cerevisiae yielded strong discriminatory performance [receiver operating characteristic (ROC)-area under the curve (AUC) = 0.92], exceeding standalone prediction with TargetP2, a predictor of N-terminal targeting peptides (ROC-AUC = 0.72). In the divergent anaerobic protist Paratrimastix pyriformis, CoMR maintained robust performance (ROC-AUC = 0.86) validated with an experimental proteome despite extreme class imbalance, achieving a precision-recall AUC of 0.183 (~78-fold enrichment over random expectation and ~10-fold improvement over TargetP2). Ablation analyses demonstrate that predictive performance is robust to individual evidence-layer removal, while overlap analyses showed that homology-based searches recovered candidates missed by targeting predictors, particularly in P. pyriformis. Overall, CoMR improves mitochondrial proteome reconstruction over targeting prediction alone and provides a reproducible workflow for predicting mitochondrial and mitochondrion-related organelle protein repertoires across eukaryotes to aid investigations of organelle evolution and proteome reduction.

Proteome↗
PubMed2025

Experimental Test of Evolutionary Safety of a CRISPR-Cas9 Gene-Drive Element.

CRISPR-Cas9 gene drives (CCGDs) are powerful tools for genetic control of wild populations, with applications from disease eradication to species conservation. However, Cas9 alone and in a complex with gRNA can cause double-stranded DNA breaks at off-target sites, which could increase the mutational load and lead to unintended loss-of-heterozygosity (LOH) events. These undesired effects raise potential concerns about the long-term evolutionary safety of CCGDs, but the magnitude of these effects is unknown. To measure how the presence of a CCGD or a Cas9 alone in the genome affects the rates of LOH events and de novo mutations, we carried out a mutation accumulation experiment in yeast Saccharomyces cerevisiae. We found no detectable effects on the genome-wide rates of mutations or LOH events. Our power calculations suggest that CCGD or Cas9 affect these rates by less than 30%, which is much less than natural variation for these traits in yeast. A more detailed examination shows that CCGD or Cas9 may alter the lengths and genomic distributions of LOH events, but the statistical support for these effects is weak. Thus, our results demonstrate that CCGDs impose at most a weak additional mutational burden in the yeast model. Although mutagenic effects of gene drives need to be further evaluated in other systems, our results add credence to the proposition that the evolutionary risks posed by well designed gene drives are likely acceptable.

Journal Article↗
PubMed2025

Mapping the transcriptional regulatory network of a fungal pathogen by exploiting transcription factor perturbation.

Cryptococcus neoformans is a deadly fungal pathogen. Upon entering a mammalian host, it deploys a voluminous polysaccharide capsule that is necessary for it to survive host defenses and maintain an infection. Capsule expansion is regulated transcriptionally, as deletion of many transcription factors (TFs) alters capsule. Thus, we set out to map the transcriptional regulatory network of C. neoformans - that is, to identify the TFs that directly regulate each gene in the genome. First, we carried out RNA-seq of 120 single-TF-deletion strains, together with wild-type controls. We then applied NetProphet3, a TF network mapping algorithm, to predict the direct functional targets of each TF. Unexpectedly, analysis of this network indicated that there are no TFs that primarily regulate genes involved in capsule formation. Rather, the TFs that play a role in deploying capsule also regulate many other genes and processes. Comparison to a TF network map we built for Saccharomyces cerevisiae, a distantly related model yeast, identified pairs of TFs that are functionally orthologous - that is, their targets are enriched for orthologous genes. In many cases, these pairs are different from the ones identified by sequence homology alone. We suggest that network analyses should be used to complement sequence comparison when searching for functionally orthologous transcription factors. Our network map can be searched and visualized at http://cryptococcus.net.

Journal Article↗
PubMed1979

Comparison on the structure and transcriptional capability of growing phase and stationary yeast chromatin: a model for reversible gene activation.

We have compared the structure of intra-nuclear and isolated chromatin from logarithmically growing yeast cells to chromatin from cells which had entered the stationary phase and ceased growing. Both chromatins show a similar nucleosomal repeat pattern, 160 bp repeat size, with staphylococcal nuclease and similar variability in repeat sizes within the genome. DNase I produces the same ladder (less than 120 b) and a quite similar extended ladder (120-300 b) which shows that both chromatins have phased nucleosomes. However, the rate of DNase I digestion of growing phase is greater than in stationary. Functionally speaking, growing phase nuclei are 5-20 times as active in the rate of endogenous transcription (all three polymerases are involved). The transcriptional and DNase I susceptibility differences noted in nuclei are maintained in sucrose gradient isolated oligonucleosomes and mononucleosomes from the two states.

Amanitins↗
PubMed1977

Fitting a model to the growth of yeast colonies.

When yeast cells reproduce, scars are left on the parent cell where the offspring has budded. Using a branching process model, it is possible to obtain the expectations of numbers of cells with 0, 1, 2, ... offspring. In this paper, theoretical results are tested against empirical data for three types of yeast cells. We examine the hypothesis that birth and death rates of cells with no previus offspring may differ from those of cells with one or more offspring. It is suggested that the oscillatory empricial results for the proportions of cells with 0, 1, 2, 3 and 4 offspring may be due to different mean budding times for these cells.

Models, Biological↗
PubMed2024

Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.

Charcot–Marie–Tooth disease↗
PubMed1978

Distribution of yeast fatty acid synthetase subunits: three-dimensional model of the enzyme.

Rabbit and goat antibodies against the isolated alpha and beta subunits of yeast fatty acid aynthetase were raised and characterized. The purified IgG fractions were studied as to their capability to precipitate their antigens and the holoenzyme and to inhibit the partial reactions involved in overall fatty acyl-CoA synthesis. The specificity of the antibodies was investigated by immunodiffusion and by immunotitration. Native enzyme was crosslinked with each of the antibodies, and dimeric and oligomeric groups of IgG-crosslinked fatty acid synthetase molecules were isolated by sucrose density gradient centrifugation. Electron microscopic investigation of the crosslinked material as well as other data led us to suggest a three-dimensional model of yeast fatty acid synthetase.

Antibody Specificity↗
PubMed2025

Predicting dynamic expression patterns in budding yeast with a fungal DNA language model.

Predicting gene expression from DNA sequence remains challenging due to complex regulatory codes. We introduce a masked DNA language model pretrained on 165 fungal genomes closely related to budding yeast that captures conserved regulatory grammar. Fine-tuning the LM on yeast RNA-seq data-including high-resolution transcriptional regulator induction time courses generated in this study-yielded Shorkie, a model that substantially improves gene expression prediction compared to baselines trained without self-supervision. Shorkie identified canonical transcription factor (TF) binding motifs and tracked their usage across induction experiments. Furthermore, Shorkie accurately predicted variant effects, outperforming leading sequence-to-expression models in cis-eQTL classification and achieving high concordance with massively parallel reporter assays. Interpretability analyses revealed Shorkie's ability to resolve promoter dynamics, splicing signals, and temporal changes in regulatory motif usage. This framework demonstrates that evolutionary-scale pretraining combined with transfer learning substantially improves our ability to decode gene regulation from sequence, providing insights into noncoding variants and regulatory networks.

Journal Article↗