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| 2. |
- Blasche, Sonja, et al.
(författare)
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Metabolic cooperation and spatiotemporal niche partitioning in a kefir microbial community
- 2021
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 6:2, s. 196-208
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Tidskriftsartikel (refereegranskat)abstract
- Microbial communities often undergo intricate compositional changes yet also maintain stable coexistence of diverse species. The mechanisms underlying long-term coexistence remain unclear as system-wide studies have been largely limited to engineered communities, ex situ adapted cultures or synthetic assemblies. Here, we show how kefir, a natural milk-fermenting community of prokaryotes (predominantly lactic and acetic acid bacteria) and yeasts (family Saccharomycetaceae), realizes stable coexistence through spatiotemporal orchestration of species and metabolite dynamics. During milk fermentation, kefir grains (a polysaccharide matrix synthesized by kefir microorganisms) grow in mass but remain unchanged in composition. In contrast, the milk is colonized in a sequential manner in which early members open the niche for the followers by making available metabolites such as amino acids and lactate. Through metabolomics, transcriptomics and large-scale mapping of inter-species interactions, we show how microorganisms poorly suited for milk survive in—and even dominate—the community, through metabolic cooperation and uneven partitioning between grain and milk. Overall, our findings reveal how inter-species interactions partitioned in space and time lead to stable coexistence.
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| 3. |
- Chen, Yu, 1990, et al.
(författare)
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Proteome constraints reveal targets for improving microbial fitness in nutrient-rich environments
- 2021
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- Cells adapt to different conditions via gene expression that tunes metabolism for maximal fitness. Constraints on cellular proteome may limit such expression strategies and introduce trade-offs. Resource allocation under proteome constraints has explained regulatory strategies in bacteria. It is unclear, however, to what extent these constraints can predict evolutionary changes, especially for microorganisms that evolved under nutrient-rich conditions, i.e., multiple available nitrogen sources, such as Lactococcus lactis. Here, we present a proteome-constrained genome-scale metabolic model of L. lactis (pcLactis) to interpret growth on multiple nutrients. Through integration of proteomics and flux data, in glucose-limited chemostats, the model predicted glucose and arginine uptake as dominant constraints at low growth rates. Indeed, glucose and arginine catabolism were found upregulated in evolved mutants. At high growth rates, pcLactis correctly predicted the observed shutdown of arginine catabolism because limited proteome availability favored lactate for ATP production. Thus, our model-based analysis is able to identify and explain the proteome constraints that limit growth rate in nutrient-rich environments and thus form targets of fitness improvement.
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| 4. |
- El-Semman, Ibrahim, 1977, et al.
(författare)
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Whole-cell modeling in yeast predicts compartment-specific proteome constraints that drive metabolic strategies
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- When conditions change, unicellular organisms rewire their metabolism to sustain cell maintenance and cellular growth. Such rewiring may be understood as resource re-allocation under cellular constraints. Eukaryal cells contain metabolically active organelles such as mitochondria, competing for cytosolic space and resources, and the nature of the relevant cellular constraints remain to be determined for such cells. Here, we present a comprehensive metabolic model of the yeast cell, based on its full metabolic reaction network extended with protein synthesis and degradation reactions. The model predicts metabolic fluxes and corresponding protein expression by constraining compartment-specific protein pools and maximising growth rate. Comparing model predictions with quantitative experimental data suggests that under glucose limitation, a mitochondrial constraint limits growth at the onset of ethanol formation-known as the Crabtree effect. Under sugar excess, however, a constraint on total cytosolic volume dictates overflow metabolism. Our comprehensive model thus identifies condition-dependent and compartment-specific constraints that can explain metabolic strategies and protein expression profiles from growth rate optimisation, providing a framework to understand metabolic adaptation in eukaryal cells.
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| 5. |
- Nilsson, Avlant, 1985, et al.
(författare)
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Metabolite Depletion Affects Flux Profiling of Cell Lines
- 2018
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Ingår i: Trends in Biochemical Sciences. - : Elsevier BV. - 1362-4326 .- 0968-0004. ; 43:6, s. 395-397
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Quantifying the rate of consumption and release of metabolites (i.e., flux profiling) has become integral to the study of cancer. The fluxes as well as the growth of the cells may be affected by metabolite depletion during cultivation.
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| 6. |
- Nilsson, Avlant, 1985, et al.
(författare)
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Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:19, s. 10294-10304
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Tidskriftsartikel (refereegranskat)abstract
- Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.
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| 7. |
- Cvijovic, Marija, 1977, et al.
(författare)
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Strategies for structuring interdisciplinary education in systems biology: An European perspective
- 2016
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Ingår i: npj Systems Biology and Applications. - : Springer Science and Business Media LLC. - 2056-7189. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Systems Biology is an approach to biology and medicine that has the potential to lead to a better understanding of how biological properties emerge from the interaction of genes, proteins, molecules, cells and organisms. The approach aims at elucidating how these interactions govern biological function by employing experimental data, mathematical models and computational simulations. As Systems Biology is inherently multidisciplinary, education within this field meets numerous hurdles including departmental barriers, availability of all required expertise locally, appropriate teaching material and example curricula. As university education at the Bachelor’s level is traditionally built upon disciplinary degrees, we believe that the most effective way to implement education in Systems Biology would be at the Master’s level, as it offers a more flexible framework. Our team of experts and active performers of Systems Biology education suggest here (i) a definition of the skills that students should acquire within a Master’s programme in Systems Biology, (ii) a possible basic educational curriculum with flexibility to adjust to different application areas and local research strengths, (iii) a description of possible career paths for students who undergo such an education, (iv) conditions that should improve the recruitment of students to such programmes and (v) mechanisms for collaboration and excellence spreading among education professionals. With the growing interest of industry in applying Systems Biology approaches in their fields, a concerted action between academia and industry is needed to build this expertise. Here we present a reflection of the European situation and expertise, where most of the challenges we discuss are universal, anticipating that our suggestions will be useful internationally. We believe that one of the overriding goals of any Systems Biology education should be a student’s ability to phrase and communicate research questions in such a manner that they can be solved by the integration of experiments and modelling, as well as to communicate and collaborate productively across different experimental and theoretical disciplines in research and development.
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