scholarly journals Bend or break: how biochemically versatile molecules enable metabolic division of labor in clonal microbial communities

Genetics ◽  
2021 ◽  
Vol 219 (2) ◽  
Author(s):  
Sriram Varahan ◽  
Sunil Laxman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Microbial Communities ◽  
Division Of Labor ◽  
Functional Specialization ◽  
Biochemical Pathways ◽  
Metabolic States ◽  
Cell Groups ◽  
Community Fitness ◽  
Metabolic Heterogeneity ◽  
Feeding Systems

Abstract In fluctuating nutrient environments, isogenic microbial cells transition into “multicellular” communities composed of phenotypically heterogeneous cells, showing functional specialization. In fungi (such as budding yeast), phenotypic heterogeneity is often described in the context of cells switching between different morphotypes (e.g., yeast to hyphae/pseudohyphae or white/opaque transitions in Candida albicans). However, more fundamental forms of metabolic heterogeneity are seen in clonal Saccharomyces cerevisiae communities growing in nutrient-limited conditions. Cells within such communities exhibit contrasting, specialized metabolic states, and are arranged in distinct, spatially organized groups. In this study, we explain how such an organization can stem from self-organizing biochemical reactions that depend on special metabolites. These metabolites exhibit plasticity in function, wherein the same metabolites are metabolized and utilized for distinct purposes by different cells. This in turn allows cell groups to function as specialized, interdependent cross-feeding systems which support distinct metabolic processes. Exemplifying a system where cells exhibit either gluconeogenic or glycolytic states, we highlight how available metabolites can drive favored biochemical pathways to produce new, limiting resources. These new resources can themselves be consumed or utilized distinctly by cells in different metabolic states. This thereby enables cell groups to sustain contrasting, even apparently impossible metabolic states with stable transcriptional and metabolic signatures for a given environment, and divide labor in order to increase community fitness or survival. We speculate on possible evolutionary implications of such metabolic specialization and division of labor in isogenic microbial communities.

scholarly journals Designing Metabolic Division of Labor in Microbial Communities

mSystems ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Meghan Thommes ◽  
Taiyao Wang ◽  
Qi Zhao ◽  
Ioannis C. Paschalidis ◽  
Daniel Segrè
Keyword(s):  
Microbial Communities ◽  
Division Of Labor ◽  
Environmental Sustainability ◽  
Computational Models ◽  
Thought Experiment ◽  
Mixed Integer ◽  
Individual Species ◽  
Large Space ◽  
Individual Organism ◽  
Trade Off

ABSTRACTMicrobes face a trade-off between being metabolically independent and relying on neighboring organisms for the supply of some essential metabolites. This balance of conflicting strategies affects microbial community structure and dynamics, with important implications for microbiome research and synthetic ecology. A “gedanken” (thought) experiment to investigate this trade-off would involve monitoring the rise of mutual dependence as the number of metabolic reactions allowed in an organism is increasingly constrained. The expectation is that below a certain number of reactions, no individual organism would be able to grow in isolation and cross-feeding partnerships and division of labor would emerge. We implemented this idealized experiment usingin silicogenome-scale models. In particular, we used mixed-integer linear programming to identify trade-off solutions in communities ofEscherichia colistrains. The strategies that we found revealed a large space of opportunities in nuanced and nonintuitive metabolic division of labor, including, for example, splitting the tricarboxylic acid (TCA) cycle into two separate halves. The systematic computation of possible solutions in division of labor for 1-, 2-, and 3-strain consortia resulted in a rich and complex landscape. This landscape displayed a nonlinear boundary, indicating that the loss of an intracellular reaction was not necessarily compensated for by a single imported metabolite. Different regions in this landscape were associated with specific solutions and patterns of exchanged metabolites. Our approach also predicts the existence of regions in this landscape where independent bacteria are viable but are outcompeted by cross-feeding pairs, providing a possible incentive for the rise of division of labor.IMPORTANCEUnderstanding how microbes assemble into communities is a fundamental open issue in biology, relevant to human health, metabolic engineering, and environmental sustainability. A possible mechanism for interactions of microbes is through cross-feeding, i.e., the exchange of small molecules. These metabolic exchanges may allow different microbes to specialize in distinct tasks and evolve division of labor. To systematically explore the space of possible strategies for division of labor, we applied advanced optimization algorithms to computational models of cellular metabolism. Specifically, we searched for communities able to survive under constraints (such as a limited number of reactions) that would not be sustainable by individual species. We found that predicted consortia partition metabolic pathways in ways that would be difficult to identify manually, possibly providing a competitive advantage over individual organisms. In addition to helping understand diversity in natural microbial communities, our approach could assist in the design of synthetic consortia.

scholarly journals Variability in Assembly of Degradation Operons for Naphthalene and its derivative, Carbaryl, Suggests Mobilization through Horizontal Gene Transfer

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 569 ◽  
Author(s):  
Phale ◽  
Shah ◽  
Malhotra
Keyword(s):  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Food Web ◽  
Microbial Communities ◽  
Metabolic Pathways ◽  
Anthropogenic Activities ◽  
Genetic Material ◽  
Genomic Islands ◽  
Biochemical Pathways ◽  
Integrative Conjugative Elements

In the biosphere, the largest biological laboratory, increased anthropogenic activities have led microbes to evolve and adapt to the changes occurring in the environment. Compounds, specifically xenobiotics, released due to such activities persist in nature and undergo bio-magnification in the food web. Some of these compounds act as potent endocrine disrupters, mutagens or carcinogens, and therefore their removal from the environment is essential. Due to their persistence, microbial communities have evolved to metabolize them partially or completely. Diverse biochemical pathways have evolved or been assembled by exchange of genetic material (horizontal gene transfer) through various mobile genetic elements like conjugative and non-conjugative plasmids, transposons, phages and prophages, genomic islands and integrative conjugative elements. These elements provide an unlimited opportunity for genetic material to be exchanged across various genera, thus accelerating the evolution of a new xenobiotic degrading phenotype. In this article, we illustrate examples of the assembly of metabolic pathways involved in the degradation of naphthalene and its derivative, Carbaryl, which are speculated to have evolved or adapted through the above-mentioned processes.

scholarly journals The Roles of Whole-Genome and Small-Scale Duplications in the Functional Specialization of Saccharomyces cerevisiae Genes

PLoS Genetics ◽  
2013 ◽  
Vol 9 (1) ◽  
pp. e1003176 ◽  
Author(s):  
Mario A. Fares ◽  
Orla M. Keane ◽  
Christina Toft ◽  
Lorenzo Carretero-Paulet ◽  
Gary W. Jones
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Small Scale ◽  
Functional Specialization ◽  
Whole Genome

scholarly journals Dual-Color Monitoring Overcomes the Limitations of Single Bioluminescent Reporters in Fast-Growing Microbes and Reveals Phase-Dependent Protein Productivity during the Metabolic Rhythms of Saccharomyces cerevisiae

2015 ◽  
Vol 81 (18) ◽  
pp. 6484-6495 ◽  
Author(s):  
Archana Krishnamoorthy ◽  
J. Brian Robertson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Gene Regulation ◽  
Inducible Promoter ◽  
Content Type ◽  
Fast Growing ◽  
Metabolic States ◽  
Dependent Protein ◽  
Protein Productivity ◽  
Yeast Metabolic Cycle ◽  
Metabolic Cycle

ABSTRACTLuciferase is a useful, noninvasive reporter of gene regulation that can be continuously monitored over long periods of time; however, its use is problematic in fast-growing microbes like bacteria and yeast because rapidly changing cell numbers and metabolic states also influence bioluminescence, thereby confounding the reporter's signal. Here we show that these problems can be overcome in the budding yeastSaccharomyces cerevisiaeby simultaneously monitoring bioluminescence from two different colors of beetle luciferase, where one color (green) reports activity of a gene of interest, while a second color (red) is stably expressed and used to continuously normalize green bioluminescence for fluctuations in signal intensity that are unrelated to gene regulation. We use this dual-luciferase strategy in conjunction with a light-inducible promoter system to test whether different phases of yeast respiratory oscillations are more suitable for heterologous protein production than others. By using pulses of light to activate production of a green luciferase while normalizing signal variation to a red luciferase, we show that the early reductive phase of the yeast metabolic cycle produces more luciferase than other phases.

scholarly journals Preface

1995 ◽  
Vol 347 (1319) ◽  
pp. 3-3
Keyword(s):  
Escherichia Coli ◽  
Saccharomyces Cerevisiae ◽  
Molecular Mechanisms ◽  
Model Systems ◽  
Biochemical Pathways ◽  
Major Threat ◽  
Environmental Agents ◽  
Living Organisms ◽  
New Research ◽  
Micro Organisms

Genomic instability is a major threat to living organisms. To counteract the damaging effects posed by endogenous and environmental agents, such as chemicals or radiation, micro-organisms devote several percent of their genome to encode proteins that function in the repair and recombination of DNA. For many years, a relatively small group of scientists have carefully delineated the molecular mechanisms of these repair processes, using the simplest model systems available, namely Escherichia coli and Saccharomyces cerevisiae . These studies, which until recently had only moderate impact outside of the field, now provide the cornerstone for exciting new research into analogous processes in hum an cells. The reason for this is the revelation that the biochemical pathways for the accurate replication, repair and recombination of DNA have been conserved through evolution.

scholarly journals Metabolite plasticity drives carbon-nitrogen resource budgeting to enable division of labor in a clonal community

2020 ◽  
Author(s):  
Sriram Varahan ◽  
Vaibhhav Sinha ◽  
Adhish Walvekar ◽  
Sandeep Krishna ◽  
Sunil Laxman
Keyword(s):  
Carbon Source ◽  
Division Of Labor ◽  
Self Organization ◽  
Bet Hedging ◽  
Nucleotide Synthesis ◽  
Metabolic Plasticity ◽  
Distinct Cell ◽  
Metabolic States ◽  
Nitrogen Budgeting

AbstractPreviously, we discovered that in glucose-limited yeast colonies, metabolic constraints drive cells into groups exhibiting gluconeogenic and glycolytic metabolic states. Here, threshold amounts of trehalose - a limiting, produced resource, controls the emergence and self-organization of the cells exhibiting the glycolytic state, by acting as a carbon source to fuel these metabolic demands (Varahan et al., 2019). We now discover that the plasticity of use of a non-limiting resource, aspartate, controls both resource production and the emergence of heterogeneous cell states, based on differential cellular metabolic budgeting. In gluconeogenic cells, aspartate provides carbon for trehalose production, while in glycolytic cells using trehalose for carbon, aspartate supplies nitrogen to drive nucleotide synthesis. This metabolic plasticity of aspartate enables carbon-nitrogen budgeting, thereby driving the biochemical self-organization of distinct cell states. Through this organization, cells in each state exhibit true division of labor, providing bet-hedging and growth/survival advantages for the whole community.

scholarly journals Designing microbial communities to maximize the thermodynamic driving force for the production of chemicals

2021 ◽  
Vol 17 (6) ◽  
pp. e1009093
Author(s):  
Pavlos Stephanos Bekiaris ◽  
Steffen Klamt
Keyword(s):  
Microbial Communities ◽  
Division Of Labor ◽  
Driving Force ◽  
Single Species ◽  
Microbial Consortia ◽  
Biotechnological Applications ◽  
Single Strain ◽  
Metabolic Burden ◽  
Thermodynamic Driving Force ◽  
Different Strains

Microbial communities have become a major research focus due to their importance for biogeochemical cycles, biomedicine and biotechnological applications. While some biotechnological applications, such as anaerobic digestion, make use of naturally arising microbial communities, the rational design of microbial consortia for bio-based production processes has recently gained much interest. One class of synthetic microbial consortia is based on specifically designed strains of one species. A common design principle for these consortia is based on division of labor, where the entire production pathway is divided between the different strains to reduce the metabolic burden caused by product synthesis. We first show that classical division of labor does not automatically reduce the metabolic burden when metabolic flux per biomass is analyzed. We then present ASTHERISC (Algorithmic Search of THERmodynamic advantages in Single-species Communities), a new computational approach for designing multi-strain communities of a single-species with the aim to divide a production pathway between different strains such that the thermodynamic driving force for product synthesis is maximized. ASTHERISC exploits the fact that compartmentalization of segments of a product pathway in different strains can circumvent thermodynamic bottlenecks arising when operation of one reaction requires a metabolite with high and operation of another reaction the same metabolite with low concentration. We implemented the ASTHERISC algorithm in a dedicated program package and applied it on E. coli core and genome-scale models with different settings, for example, regarding number of strains or demanded product yield. These calculations showed that, for each scenario, many target metabolites (products) exist where a multi-strain community can provide a thermodynamic advantage compared to a single strain solution. In some cases, a production with sufficiently high yield is thermodynamically only feasible with a community. In summary, the developed ASTHERISC approach provides a promising new principle for designing microbial communities for the bio-based production of chemicals.

scholarly journals Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4699
Author(s):  
Marina Fukano ◽  
Morag Park ◽  
Geneviève Deblois
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Metabolic Flexibility ◽  
Extrinsic Factors ◽  
Breast Tumours ◽  
Cancer Heterogeneity ◽  
Energy Demands ◽  
Metabolic States ◽  
Metabolic Heterogeneity ◽  
High Level

Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.

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