For thousands of years, the yeast Saccharomyces cerevisiae (S. cerevisiae) has served as a cell factory for the production of bread, beer, and wine. In more recent years, this yeast has also served ...as a cell factory for producing many different fuels, chemicals, food ingredients, and pharmaceuticals. S. cerevisiae, however, has also served as a very important model organism for studying eukaryal biology, and even today many new discoveries, important for the treatment of human diseases, are made using this yeast as a model organism. Here a brief review of the use of S. cerevisiae as a model organism for studying eukaryal biology, its use as a cell factory, and how advances in systems biology underpin developments in both these areas, is provided.
Through engineering yeast metabolism it is possible to produce many different molecules finding applications as biofuels, chemicals, and pharmaceuticals. Relying on the extensive knowledge base of yeast, due to its many years of use as a model organism, has assisted in improving new design strategies, and also the advancement in systems biology has enabled the improved design of efficient cell factories.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Systems Biology of Metabolism Nielsen, Jens
Annual review of biochemistry,
06/2017, Volume:
86, Issue:
1
Journal Article
Peer reviewed
Metabolism is highly complex and involves thousands of different connected reactions; it is therefore necessary to use mathematical models for holistic studies. The use of mathematical models in ...biology is referred to as systems biology. In this review, the principles of systems biology are described, and two different types of mathematical models used for studying metabolism are discussed: kinetic models and genome-scale metabolic models. The use of different omics technologies, including transcriptomics, proteomics, metabolomics, and fluxomics, for studying metabolism is presented. Finally, the application of systems biology for analyzing global regulatory structures, engineering the metabolism of cell factories, and analyzing human diseases is discussed.
Systems biology uses mathematical models to analyze large datasets and simulate system behavior. It enables integrative analysis of different types of data and can thereby provide new insight into ...complex biological systems. Here will be discussed the challenges of using systems medicine for advancing the development of personalized and precision medicine to treat metabolic diseases like insulin resistance, obesity, NAFLD, NASH, and cancer. It will be illustrated how the concept of genome-scale metabolic models can be used for integrative analysis of big data with the objective of identifying novel biomarkers that are foundational for personalized and precision medicine.
The advancement of personalized medicine is hindered by a lack of good prognostic biomarkers. Here Nielsen discusses how integrative analysis of big data using genome-scale metabolic models can advance the development of personalized and precision medicine to treat metabolic diseases like insulin resistance, obesity, NAFLD, NASH, and cancer.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An iterative procedure for numerical prediction of long-term degradation of railway track geometry (longitudinal level) due to accumulated differential settlement of ballast/subgrade is presented. ...The procedure is based on a time-domain model of dynamic vehicle–track interaction to calculate the contact loads between sleepers and ballast in the short-term, which are then used in an empirical model to determine the settlement of ballast/subgrade below each sleeper in the long-term. The number of load cycles (wheel passages) accounted for in each iteration step is determined by an adaptive step length given by a maximum settlement increment. To reduce the computational effort for the simulations of dynamic vehicle–track interaction, complex-valued modal synthesis with a truncated modal set is applied for the linear subset of the discretely supported track model with non-proportional spatial distribution of viscous damping. Gravity loads and state-dependent vehicle, track and wheel–rail contact conditions are accounted for as external loads on the modal model, including situations involving loss of (and recovered) wheel–rail contact, impact between hanging sleeper and ballast, and/or a prescribed variation of non-linear track support stiffness properties along the track model. The procedure is demonstrated by calculating the degradation of longitudinal level over time as initiated by a prescribed initial local rail irregularity (dipped welded rail joint).
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cells require energy for growth and maintenance and have evolved to have multiple pathways to produce energy in response to varying conditions. A basic question in this context is how cells organize ...energy metabolism, which is, however, challenging to elucidate due to its complexity, i.e., the energy-producing pathways overlap with each other and even intertwine with biomass formation pathways. Here, we propose a modeling concept that decomposes energy metabolism into biomass formation and ATP-producing pathways. The latter can be further decomposed into a high-yield and a low-yield pathway. This enables independent estimation of protein efficiency for each pathway. With this concept, we modeled energy metabolism for Escherichia coli and Saccharomyces cerevisiae and found that the high-yield pathway shows lower protein efficiency than the low-yield pathway. Taken together with a fixed protein constraint, we predict overflow metabolism in E. coli and the Crabtree effect in S. cerevisiae, meaning that energy metabolism is sufficient to explain the metabolic switches. The static protein constraint is supported by the findings that protein mass of energy metabolism is conserved across conditions based on absolute proteomics data. This also suggests that enzymes may have decreased saturation or activity at low glucose uptake rates. Finally, our analyses point out three ways to improve growth, i.e., increasing protein allocation to energy metabolism, decreasing ATP demand, or increasing activity for key enzymes.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Natural product biosynthesis is inherently linked with the primary metabolism in terms of providing precursors and co-factors. Thus, even though it is important to improve the performance of natural ...product biosynthetic enzymes in building efficient cell factories, it is equally important to engineer the central carbon metabolism, such that this is adjusted to meet the biosynthetic demand of the desired product.
Natural product biosynthesis is inherently linked with the primary metabolism in terms of providing precursors and co-factors.
The dependence on fossil fuels has caused excessive emissions of greenhouse gases (GHGs), leading to climate changes and global warming. Even though the expansion of electricity generation will ...enable a wider use of electric vehicles, biotechnology represents an attractive route for producing high-density liquid transportation fuels that can reduce GHG emissions from jets, long-haul trucks and ships. Furthermore, to achieve immediate alleviation of the current environmental situation, besides reducing carbon footprint it is urgent to develop technologies that transform atmospheric CO
2
into fossil fuel replacements. The integration of bio-catalysis and electrocatalysis (bio-electrocatalysis) provides such a promising avenue to convert CO
2
into fuels and chemicals with high-chain lengths. Following an overview of different mechanisms that can be used for CO
2
fixation, we will discuss crucial factors for electrocatalysis with a special highlight on the improvement of electron-transfer kinetics, multi-dimensional electrocatalysts and their hybrids, electrolyser configurations, and the integration of electrocatalysis and bio-catalysis. Finally, we prospect key advantages and challenges of bio-electrocatalysis, and end with a discussion of future research directions.
The integration of bio-catalysis and electrocatalysis advanced CO
2
utilization.
Filamentous fungi produce a wide range of bioactive compounds with important pharmaceutical applications, such as antibiotic penicillins and cholesterol-lowering statins. However, less attention has ...been paid to fungal secondary metabolites compared to those from bacteria. In this study, we sequenced the genomes of 9 Penicillium species and, together with 15 published genomes, we investigated the secondary metabolism of Penicillium and identified an immense, unexploited potential for producing secondary metabolites by this genus. A total of 1,317 putative biosynthetic gene clusters (BGCs) were identified, and polyketide synthase and non-ribosomal peptide synthetase based BGCs were grouped into gene cluster families and mapped to known pathways. The grouping of BGCs allowed us to study the evolutionary trajectory of pathways based on 6-methylsalicylic acid (6-MSA) synthases. Finally, we cross-referenced the predicted pathways with published data on the production of secondary metabolites and experimentally validated the production of antibiotic yanuthones in Penicillia and identified a previously undescribed compound from the yanuthone pathway. This study is the first genus-wide analysis of the genomic diversity of Penicillia and highlights the potential of these species as a source of new antibiotics and other pharmaceuticals.
Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more ...plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.
The yeast Saccharomyces cerevisiae is a widely used cell factory for the production of fuels, chemicals, and pharmaceuticals. The use of this cell factory for cost-efficient production of novel fuels ...and chemicals requires high yields and low by-product production. Many industrially interesting chemicals are biosynthesized from acetyl coenzyme A (acetyl-CoA), which serves as a central precursor metabolite in yeast. To ensure high yields in production of these chemicals, it is necessary to engineer the central carbon metabolism so that ethanol production is minimized (or eliminated) and acetyl-CoA can be formed from glucose in high yield. Here the perspective of generating yeast platform strains that have such properties is discussed in the context of a major breakthrough with expression of a functional pyruvate dehydrogenase complex in the cytosol.
PDF
