Integrating systemic and molecular levels to infer key drivers sustaining metabolic adaptations
| Autor: | Pedro de Atauri, Josep Tarragó-Celada, Effrosyni Karakitsou, Marta Cascante, Carles Foguet, Míriam Tarrado-Castellarnau, Josep J. Centelles |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Enzyme Metabolism Metabolic adaptation Gene Expression Biochemistry 0302 clinical medicine Molecular level Drug Metabolism Protein kinases Metabolites Medicine and Health Sciences Biology (General) Enzyme Chemistry chemistry.chemical_classification Ecology Kinase Stoichiometry Metabolisme Enzymes Gene Expression Regulation Neoplastic Chemistry Computational Theory and Mathematics Oncology 030220 oncology & carcinogenesis Modeling and Simulation Colonic Neoplasms Physical Sciences Glycolysis Metabolic Networks and Pathways Network Analysis Research Article Gens Computer and Information Sciences QH301-705.5 Biochemical Phenomena Systems Theory Computational biology Biology Models Biological Proof of Concept Study 03 medical and health sciences Cellular and Molecular Neuroscience Metabolic Networks Càncer colorectal Genetics Humans Metabolomics Computer Simulation Pharmacokinetics Molecular Biology Gene Protein Kinase Inhibitors Ecology Evolution Behavior and Systematics Pharmacology Computational Biology Cyclin-Dependent Kinase 4 Biology and Life Sciences Cancers and Neoplasms Proteins Transporter Cyclin-Dependent Kinase 6 HCT116 Cells Colorectal cancer Metabolic Flux Analysis Proteïnes quinases Kinetics 030104 developmental biology Enzyme Metabolism chemistry Genes Metabolic control analysis Linear Models Enzymology Drug metabolism |
| Zdroj: | PLoS Computational Biology PLoS Computational Biology, Vol 17, Iss 7, p e1009234 (2021) Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response. Author summary Deciphering the essential events in the reprogramming of metabolic networks subjected to complex perturbations, including the response to pharmacological treatments in multifactorial diseases like cancer, is crucial for the design of efficient therapies. Yet, tools to infer the molecular drivers sustaining such metabolic responses remain elusive for large metabolic networks. Here we develop an efficient computational strategy that integrates measured changes at systemic and molecular levels and combines metabolic control analysis with linear programming tools to infer key molecular drivers sustaining the metabolic adaptations to complex perturbations, such as an antitumoral drug therapy. The collective behavior is approximated using linear expressions where the adaptation of systemic concentrations and fluxes to a perturbation is described as a function of the molecular reprogramming of transport and enzyme activities. Starting from measured changes in fluxes and concentrations, we identify changes in the reprogramming of transporter and enzyme activities that are required to orchestrate the metabolic adaptation of colon cancer cells to a cell cycle inhibitor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|