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Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism
Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydroge...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society Publishing
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666243/ https://www.ncbi.nlm.nih.gov/pubmed/29134060 http://dx.doi.org/10.1098/rsos.170360 |
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author | Eyassu, Filmon Angione, Claudio |
author_facet | Eyassu, Filmon Angione, Claudio |
author_sort | Eyassu, Filmon |
collection | PubMed |
description | Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia. Our results characterize the activity of pyruvate dehydrogenase and its decline during hypoxia. This results in lactate accumulation, consistent with recent hypoxia studies and a well-known feature in cancer metabolism. We apply machine-learning techniques on the flux datasets to identify reactions that drive these variations. We also identify distinct features on the structure of the variables and individual metabolic components in the switch from normoxia to hypoxia. Our results provide a framework for future studies by integrating multi-omics data to predict condition-specific metabolic phenotypes under hypoxia. |
format | Online Article Text |
id | pubmed-5666243 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Royal Society Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-56662432017-11-13 Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism Eyassu, Filmon Angione, Claudio R Soc Open Sci Computer Science Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia. Our results characterize the activity of pyruvate dehydrogenase and its decline during hypoxia. This results in lactate accumulation, consistent with recent hypoxia studies and a well-known feature in cancer metabolism. We apply machine-learning techniques on the flux datasets to identify reactions that drive these variations. We also identify distinct features on the structure of the variables and individual metabolic components in the switch from normoxia to hypoxia. Our results provide a framework for future studies by integrating multi-omics data to predict condition-specific metabolic phenotypes under hypoxia. The Royal Society Publishing 2017-10-25 /pmc/articles/PMC5666243/ /pubmed/29134060 http://dx.doi.org/10.1098/rsos.170360 Text en © 2017 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. |
spellingShingle | Computer Science Eyassu, Filmon Angione, Claudio Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title | Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title_full | Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title_fullStr | Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title_full_unstemmed | Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title_short | Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
title_sort | modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism |
topic | Computer Science |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666243/ https://www.ncbi.nlm.nih.gov/pubmed/29134060 http://dx.doi.org/10.1098/rsos.170360 |
work_keys_str_mv | AT eyassufilmon modellingpyruvatedehydrogenaseunderhypoxiaanditsroleincancermetabolism AT angioneclaudio modellingpyruvatedehydrogenaseunderhypoxiaanditsroleincancermetabolism |