scholarly journals Phenotype-based cell-specific metabolic modeling reveals metabolic liabilities of cancer

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Keren Yizhak ◽  
Edoardo Gaude ◽  
Sylvia Le Dévédec ◽  
Yedael Y Waldman ◽  
Gideon Y Stein ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Modeling ◽  
Molecular Data ◽  
Metabolic Effects ◽  
Proof Of Concept ◽  
Phenotypic Data ◽  
Experimental Proof ◽  
Physiological Models ◽  
Genome Scale ◽  
Computational Basis

Utilizing molecular data to derive functional physiological models tailored for specific cancer cells can facilitate the use of individually tailored therapies. To this end we present an approach termed PRIME for generating cell-specific genome-scale metabolic models (GSMMs) based on molecular and phenotypic data. We build >280 models of normal and cancer cell-lines that successfully predict metabolic phenotypes in an individual manner. We utilize this set of cell-specific models to predict drug targets that selectively inhibit cancerous but not normal cell proliferation. The top predicted target, MLYCD, is experimentally validated and the metabolic effects of MLYCD depletion investigated. Furthermore, we tested cell-specific predicted responses to the inhibition of metabolic enzymes, and successfully inferred the prognosis of cancer patients based on their PRIME-derived individual GSMMs. These results lay a computational basis and a counterpart experimental proof of concept for future personalized metabolic modeling applications, enhancing the search for novel selective anticancer therapies.

scholarly journals In silicoidentification of metabolic enzyme drug targets inBurkholderia pseudomallei

2015 ◽  
Author(s):  
Jean F. Challacombe
Keyword(s):  
In Silico ◽  
Drug Targets ◽  
Culture Media ◽  
Metabolic Modeling ◽  
Host Cells ◽  
Natural Resistance ◽  
Metabolic Enzyme ◽  
Chronic Infections ◽  
Genome Scale ◽  
Nutrient Conditions

AbstractThe intracellular pathogenBurkholderia pseudomallei,which is endemic to parts of southeast Asia and northern Australia, causes the disease melioidosis. Although acute infections can be treated with antibiotics, melioidosis is difficult to cure, and some patients develop chronic infections or a recrudescence of the disease months or years after treatment of the initial infection.B. pseudomalleistrains have a high level of natural resistance to a variety of antibiotics, and with limited options for new antibiotics on the horizon, new alternatives are needed. The aim of the present study was to characterize the metabolic capabilities ofB. pseudomallei, identify metabolites crucial for pathogen survival, understand the metabolic interactions that occur between pathogen and host cells, and determine if metabolic enzymes produced by the pathogen might be potential antibacterial targets. This aim was accomplished through genome scale metabolic modeling under different external conditions: 1) including all nutrients that could be consumed by the model, and 2) providing only the nutrients available in culture media. Using this approach, candidate chokepoint enzymes were identified, then knocked outin silicounder the different nutrient conditions. The effect of each knockout on the metabolic network was examined. When five of the candidate chokepoints were knocked outin silico, the flux through theB. pseudomalleinetwork was decreased, depending on the nutrient conditions. These results demonstrate the utility of genome-scale metabolic modeling methods for drug target identification inB. pseudomallei.

scholarly journals Genome-Scale Metabolic Modeling Enables In-Depth Understanding of Big Data

Metabolites ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 14
Author(s):  
Anurag Passi ◽  
Juan D. Tibocha-Bonilla ◽  
Manish Kumar ◽  
Diego Tec-Campos ◽  
Karsten Zengler ◽  
...  
Keyword(s):  
Machine Learning ◽  
Big Data ◽  
Metabolic Pathways ◽  
Drug Targets ◽  
Metabolic Modeling ◽  
Annotation Data ◽  
Dynamic Resolution ◽  
Different Types ◽  
Eukaryotic Organisms ◽  
Genome Scale

Genome-scale metabolic models (GEMs) enable the mathematical simulation of the metabolism of archaea, bacteria, and eukaryotic organisms. GEMs quantitatively define a relationship between genotype and phenotype by contextualizing different types of Big Data (e.g., genomics, metabolomics, and transcriptomics). In this review, we analyze the available Big Data useful for metabolic modeling and compile the available GEM reconstruction tools that integrate Big Data. We also discuss recent applications in industry and research that include predicting phenotypes, elucidating metabolic pathways, producing industry-relevant chemicals, identifying drug targets, and generating knowledge to better understand host-associated diseases. In addition to the up-to-date review of GEMs currently available, we assessed a plethora of tools for developing new GEMs that include macromolecular expression and dynamic resolution. Finally, we provide a perspective in emerging areas, such as annotation, data managing, and machine learning, in which GEMs will play a key role in the further utilization of Big Data.

scholarly journals Cellular Genome-scale Metabolic Modeling Identifies New Potential Drug Targets Against Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Oveis Jamialahmadi ◽  
Ehsan Salehabadi ◽  
Sameereh Hashemi-Najafabadi ◽  
Ehsan Motamedian ◽  
Fatemeh Bagheri ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Drug Targets ◽  
Cancer Metabolism ◽  
Essential Gene ◽  
Metabolic Modeling ◽  
Essential Genes ◽  
Potential Drug ◽  
Genome Scale ◽  
Potential Drug Targets

Abstract Hepatocellular carcinoma is the third leading cause of cancer related mortality worldwide. Often this hepatic cancer is associated with fatty liver disease and insulin resistance with genetic predisposition are its major driver. Genome-scale metabolic modeling (GEM) is a promising approach to understand cancer metabolism and to identify new drug targets. Here, we used TRFBA-CORE, an algorithm generating a model using key growth-correlated reactions. Specifically, we generated a HepG2 cell-specific GEM by integrating this cell line transcriptomic data with a generic human metabolic model to predict potential drug targets for hepatocellular carcinoma (HCC). A total of 108 essential genes for growth were predicted by TRFBA-CORE. These genes were enriched for metabolic pathways involved in cholesterol, sterols and steroids biosynthesis. Furthermore, we silenced a predicted essential gene, 11-beta dehydrogenase hydroxysteroid type 2 (HSD11B2), in HepG2 cells resulting in a reduction in cell viability. To further identify novel potential drug targets in HCC, we examined the effect of 9 drugs targeting the essential genes, and observed that most drugs inhibited the growth of HepG2 cells. Interestingly, some of these drugs in this model performed better than Sorafenib, the first line therapeutic against HCC.

Computational medicine: quantitative modeling of complex diseases

2019 ◽  
Vol 21 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Basant K Tiwary
Keyword(s):  
Drug Targets ◽  
Computational Models ◽  
Complex Diseases ◽  
Molecular Data ◽  
Quantitative Model ◽  
Support Vector ◽  
Biomedical Data ◽  
Biological Organization ◽  
Recent Advances ◽  
Genome Scale

Abstract Biological complex systems are composed of numerous components that interact within and across different scales. The ever-increasing generation of high-throughput biomedical data has given us an opportunity to develop a quantitative model of nonlinear biological systems having implications in health and diseases. Multidimensional molecular data can be modeled using various statistical methods at different scales of biological organization, such as genome, transcriptome and proteome. I will discuss recent advances in the application of computational medicine in complex diseases such as network-based studies, genome-scale metabolic modeling, kinetic modeling and support vector machines with specific examples in the field of cancer, psychiatric disorders and type 2 diabetes. The recent advances in translating these computational models in diagnosis and identification of drug targets of complex diseases are discussed, as well as the challenges researchers and clinicians are facing in taking computational medicine from the bench to bedside.

scholarly journals Integration of machine learning and genome-scale metabolic modeling identifies multi-omics biomarkers for radiation resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joshua E. Lewis ◽  
Melissa L. Kemp
Keyword(s):  
Machine Learning ◽  
Metabolic Flux ◽  
Metabolic Modeling ◽  
The Cancer Genome Atlas ◽  
Radiation Response ◽  
Metabolomics Data ◽  
Machine Learning Classifiers ◽  
Learning Classifiers ◽  
Metabolic Biomarkers ◽  
Genome Scale

AbstractResistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients.

Performance of a points-based scoring system for assessing species limits in birds

The Auk ◽  
2021 ◽  
Author(s):  
Joseph A Tobias ◽  
Paul F Donald ◽  
Rob W Martin ◽  
Stuart H M Butchart ◽  
Nigel J Collar
Keyword(s):  
Strong Support ◽  
Molecular Data ◽  
Sympatric Species ◽  
Global Scale ◽  
Training Set ◽  
Species Limits ◽  
Phenotypic Data ◽  
Fast Tracking ◽  
Extinction Rates ◽  
Phenotypic Divergence

AbstractSpecies are fundamental to biology, conservation, and environmental legislation; yet, there is often disagreement on how and where species limits should be drawn. Even sophisticated molecular methods have limitations, particularly in the context of geographically isolated lineages or inadequate sampling of loci. With extinction rates rising, methods are needed to assess species limits rapidly but robustly. Tobias et al. devised a points-based system to compare phenotypic divergence between taxa against the level of divergence in sympatric species, establishing a threshold to guide taxonomic assessments at a global scale. The method has received a mixed reception. To evaluate its performance, we identified 397 novel taxonomic splits from 328 parent taxa made by application of the criteria (in 2014‒2016) and searched for subsequent publications investigating the same taxa with molecular and/or phenotypic data. Only 71 (18%) novel splits from 60 parent taxa have since been investigated by independent studies, suggesting that publication of splits underpinned by the criteria in 2014–2016 accelerated taxonomic decisions by at least 33 years. In the evaluated cases, independent analyses explicitly or implicitly supported species status in 62 (87.3%) of 71 splits, with the level of support increasing to 97.2% when excluding subsequent studies limited only to molecular data, and reaching 100% when the points-based criteria were applied using recommended sample sizes. Despite the fact that the training set used to calibrate the criteria was heavily weighted toward passerines, splits of passerines and non-passerines received equally strong support from independent research. We conclude that the method provides a useful tool for quantifying phenotypic divergence and fast-tracking robust taxonomic decisions at a global scale.

scholarly journals Metabolic Modeling of Pectobacterium parmentieri SCC3193 Provides Insights into Metabolic Pathways of Plant Pathogenic Bacteria

2019 ◽  
Vol 7 (4) ◽  
pp. 101 ◽  
Author(s):  
Sabina Zoledowska ◽  
Luana Presta ◽  
Marco Fondi ◽  
Francesca Decorosi ◽  
Luciana Giovannetti ◽  
...  
Keyword(s):  
In Silico ◽  
Pathogenic Bacteria ◽  
Metabolic Modeling ◽  
Metabolic Model ◽  
Metabolic Adaptation ◽  
Ecological Niches ◽  
Plant Colonization ◽  
Phenotypic Data ◽  
Plant Pathogenic Bacteria ◽  
Metabolic Versatility

Understanding plant–microbe interactions is crucial for improving plants’ productivity and protection. Constraint-based metabolic modeling is one of the possible ways to investigate the bacterial adaptation to different ecological niches and may give insights into the metabolic versatility of plant pathogenic bacteria. We reconstructed a raw metabolic model of the emerging plant pathogenic bacterium Pectobacterium parmentieri SCC3193 with the use of KBase. The model was curated by using inParanoind and phenotypic data generated with the use of the OmniLog system. Metabolic modeling was performed through COBRApy Toolbox v. 0.10.1. The curated metabolic model of P. parmentieri SCC3193 is highly reliable, as in silico obtained results overlapped up to 91% with experimental data on carbon utilization phenotypes. By mean of flux balance analysis (FBA), we predicted the metabolic adaptation of P. parmentieri SCC3193 to two different ecological niches, relevant for the persistence and plant colonization by this bacterium: soil and the rhizosphere. We performed in silico gene deletions to predict the set of essential core genes for this bacterium to grow in such environments. We anticipate that our metabolic model will be a valuable element for defining a set of metabolic targets to control infection and spreading of this plant pathogen.

scholarly journals Identification of potential drug targets in Salmonella enterica sv. Typhimurium using metabolic modelling and experimental validation

Microbiology ◽  
2014 ◽  
Vol 160 (6) ◽  
pp. 1252-1266 ◽  
Author(s):  
Hassan B. Hartman ◽  
David A. Fell ◽  
Sergio Rossell ◽  
Peter Ruhdal Jensen ◽  
Martin J. Woodward ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Energy Demand ◽  
Drug Targets ◽  
Minimal Medium ◽  
Model Organism ◽  
Metabolic Model ◽  
Scale Model ◽  
Glucose Minimal Medium ◽  
A Genome ◽  
Genome Scale

Salmonella enterica sv. Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of S. Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in the energy demand while growing in glucose minimal medium. By grouping reactions with similar flux responses, a subnetwork of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions that when removed from the genome-scale model interfered with energy and biomass generation. Eleven such sets were found to be essential for the production of biomass precursors. Experimental investigation of seven of these showed that knockouts of the associated genes resulted in attenuated growth for four pairs of reactions, whilst three single reactions were shown to be essential for growth.

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