Molecular Systems Biology

Journal: Molecular Systems Biology

Abbreviation

Mol Syst Biol

Publisher

Nature

ISSN

1744-4292

Show all metadata

Search Results

Publications 1 - 10 of 62

Pan-Cancer landscape of protein activities identifies drivers of signalling dysregulation and patient survival
Sousa, Abel; Dugourd, Aurelien; Memon, Danish; et al. (2023)
Molecular Systems Biology
Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours have been extensively characterised, the measurements of protein activities have been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics measurements for 1,110 tumours and 77 cell lines that we used to estimate activity changes in 218 kinases and 292 TFs. Co-regulation of kinase and TF activities reflects previously known regulatory relationships and allows us to dissect genetic drivers of signalling changes in cancer. We find that loss-of-function mutations are not often associated with the dysregulation of downstream targets, suggesting frequent compensatory mechanisms. Finally, we identified the activities most differentially regulated in cancer subtypes and showed how these can be linked to differences in patient survival. Our results provide broad insights into the dysregulation of protein activities in cancer and their contribution to disease severity.
Absolute quantification of microbial proteomes at different states by directed mass spectrometry
Schmidt, Alexander; Beck, Martin; Malmström, Johan; et al. (2011)
Molecular Systems Biology
Over the past decade, liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) has evolved into the main proteome discovery technology. Up to several thousand proteins can now be reliably identified from a sample and the relative abundance of the identified proteins can be determined across samples. However, the remeasurement of substantially similar proteomes, for example those generated by perturbation experiments in systems biology, at high reproducibility and throughput remains challenging. Here, we apply a directed MS strategy to detect and quantify sets of pre‐determined peptides in tryptic digests of cells of the human pathogen Leptospira interrogans at 25 different states. We show that in a single LC–MS/MS experiment around 5000 peptides, covering 1680 L. interrogans proteins, can be consistently detected and their absolute expression levels estimated, revealing new insights about the proteome changes involved in pathogenic progression and antibiotic defense of L. interrogans. This is the first study that describes the absolute quantitative behavior of any proteome over multiple states, and represents the most comprehensive proteome abundance pattern comparison for any organism to date.
One-shot 13C15N-metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux
Slater, Khushboo Borah; Beyss, Martin; Xu, Ye; et al. (2023)
Molecular Systems Biology
Metabolic flux is the final output of cellular regulation and has been extensively studied for carbon but much less is known about nitrogen, which is another important building block for living organisms. For the tuberculosis pathogen, this is particularly important in informing the development of effective drugs targeting the pathogen's metabolism. Here we performed (CN)-C-13-N-15 dual isotopic labeling of Mycobacterium bovis BCG steady state cultures, quantified intracellular carbon and nitrogen fluxes and inferred reaction bidirectionalities. This was achieved by model scope extension and refinement, implemented in a multi-atom transition model, within the statistical framework of Bayesian model averaging (BMA). Using BMA-based (CN)-C-13-N-15-metabolic flux analysis, we jointly resolve carbon and nitrogen fluxes quantitatively. We provide the first nitrogen flux distributions for amino acid and nucleotide biosynthesis in mycobacteria and establish glutamate as the central node for nitrogen metabolism. We improved resolution of the notoriously elusive anaplerotic node in central carbon metabolism and revealed possible operation modes. Our study provides a powerful and statistically rigorous platform to simultaneously infer carbon and nitrogen metabolism in any biological system.
Tradeoff between enzyme and metabolite efficiency maintains metabolic homeostasis upon perturbations in enzyme capacity
Fendt, Sarah-Maria; Buescher, Joerg M.; Rudroff, Florian; et al. (2010)
Molecular Systems Biology
What is the relationship between enzymes and metabolites, the two major constituents of metabolic networks? We propose three alternative relationships between enzyme capacity and metabolite concentration alterations based on a Michaelis–Menten kinetic; that is enzyme capacities, metabolite concentrations, or both could limit the metabolic reaction rates. These relationships imply different correlations between changes in enzyme capacity and metabolite concentration, which we tested by quantifying metabolite, transcript, and enzyme abundances upon local (single‐enzyme modulation) and global (GCR2 transcription factor mutant) perturbations in Saccharomyces cerevisiae. Our results reveal an inverse relationship between fold‐changes in substrate metabolites and their catalyzing enzymes. These data provide evidence for the hypothesis that reaction rates are jointly limited by enzyme capacity and metabolite concentration. Hence, alteration in one network constituent can be efficiently buffered by converse alterations in the other constituent, implying a passive mechanism to maintain metabolic homeostasis upon perturbations in enzyme capacity.
Metabolic constraints on the evolution of antibiotic resistance
Zampieri, Mattia; Enke, Tim; Chubukov, Victor; et al. (2017)
Molecular Systems Biology
Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in terms of speed and mode of resistance acquisition. To interpret and explore the space of metabolome changes, we developed a novel constraint‐based modeling approach using the concept of shadow prices. This analysis, together with genome resequencing of resistant populations, identified condition‐dependent compensatory mechanisms of antibiotic resistance, such as the shift from respiratory to fermentative metabolism of glucose upon overexpression of efflux pumps. Moreover, metabolome‐based predictions revealed emerging weaknesses in resistant strains, such as the hypersensitivity to fosfomycin of ampicillin‐resistant strains. Overall, resolving metabolic adaptation throughout antibiotic‐driven evolutionary trajectories opens new perspectives in the fight against emerging antibiotic resistance.
Putative regulatory sites unraveled by network-embedded thermodynamic analysis of metabolome data
Kümmel, Anne; Panke, Sven; Heinemann, Matthias (2006)
Molecular Systems Biology
Comprehensive quantitative analysis of central carbon and amino-acid metabolism in Saccharomyces cerevisiae under multiple conditions by targeted proteomics
Costenoble, Roeland; Picotti, Paola; Reiter, Lukas; et al. (2011)
Molecular Systems Biology
Decades of biochemical research have identified most of the enzymes that catalyze metabolic reactions in the yeast Saccharomyces cerevisiae. The adaptation of metabolism to changing nutritional conditions, in contrast, is much less well understood. As an important stepping stone toward such understanding, we exploit the power of proteomics assays based on selected reaction monitoring (SRM) mass spectrometry to quantify abundance changes of the 228 proteins that constitute the central carbon and amino‐acid metabolic network in the yeast Saccharomyces cerevisiae, at five different metabolic steady states. Overall, 90% of the targeted proteins, including families of isoenzymes, were consistently detected and quantified in each sample, generating a proteomic data set that represents a nutritionally perturbed biological system at high reproducibility. The data set is near comprehensive because we detect 95–99% of all proteins that are required under a given condition. Interpreted through flux balance modeling, the data indicate that S. cerevisiae retains proteins not necessarily used in a particular environment. Further, the data suggest differential functionality for several metabolic isoenzymes.
The interdependence of transcript and protein abundance: New data-new complexities
Liu, Yansheng; Aebersold, Ruedi (2016)
Molecular Systems Biology
The relative contribution of transcriptional and translational regulation in gene expression control has been intensely debated and remains a challenging question. Recent reports have suggested that protein abundance in mammalian cells is primarily controlled at the transcript‐level. In their recent work, Cheng et al (2016) determined the proteomic and transcriptomic changes in cells responding to endoplasmic reticulum (ER) stress. Their analyses indicate that the ER stress response is significantly controlled at both the transcript and protein levels.
Emergence of robust growth laws from optimal regulation of ribosome synthesis
Scott, Matthew; Klumpp, Stefan; Mateescu, Eduard M.; et al. (2014)
Molecular Systems Biology
Bacteria must constantly adapt their growth to changes in nutrient availability; yet despite large‐scale changes in protein expression associated with sensing, adaptation, and processing different environmental nutrients, simple growth laws connect the ribosome abundance and the growth rate. Here, we investigate the origin of these growth laws by analyzing the features of ribosomal regulation that coordinate proteome‐wide expression changes with cell growth in a variety of nutrient conditions in the model organism Escherichia coli. We identify supply‐driven feedforward activation of ribosomal protein synthesis as the key regulatory motif maximizing amino acid flux, and autonomously guiding a cell to achieve optimal growth in different environments. The growth laws emerge naturally from the robust regulatory strategy underlying growth rate control, irrespective of the details of the molecular implementation. The study highlights the interplay between phenomenological modeling and molecular mechanisms in uncovering fundamental operating constraints, with implications for endogenous and synthetic design of microorganisms.
Subspecies in the global human gut microbiome
Costea, Paul I.; Coelho, Luis P.; Sunagawa, Shinichi; et al. (2017)
Molecular Systems Biology
Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.

Publications 1 - 10 of 62

Journal: Molecular Systems Biology

Abbreviation

Publisher

Journal Volumes

ISSN

Description

Filters

Search Results