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Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis

Complex feedback regulation patterns shape the cellular metabolic response to external or internal perturbations. We propose here a framework consisting of a sampling-based metabolic control analysis of kinetic models to investigate the modes of regulatory interplay in metabolic functions. NADPH hom...

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Detalles Bibliográficos
Autores principales: Pfeuty, Benjamin, Hurbain, Julien, Thommen, Quentin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146214/
https://www.ncbi.nlm.nih.gov/pubmed/37110144
http://dx.doi.org/10.3390/metabo13040485
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author Pfeuty, Benjamin
Hurbain, Julien
Thommen, Quentin
author_facet Pfeuty, Benjamin
Hurbain, Julien
Thommen, Quentin
author_sort Pfeuty, Benjamin
collection PubMed
description Complex feedback regulation patterns shape the cellular metabolic response to external or internal perturbations. We propose here a framework consisting of a sampling-based metabolic control analysis of kinetic models to investigate the modes of regulatory interplay in metabolic functions. NADPH homeostasis, for instance in a context of oxidative stress, is an example of metabolic function that involves multiple feedback regulations which raises the issue of their concerted action. Our computational framework allows us to characterize both respective and combined effects of regulations, distinguishing between synergistic versus complementary modes of regulatory crosstalk. Synergistic regulation of G6PD enzymes and PGI enzymes is mediated by congruent effects between concentration sensitivities and reaction elasticities. Complementary regulation of pentose phosphate pathway and lower glycolysis relates to metabolic state-dependent range of regulation efficiency. These cooperative effects are shown to significantly improve metabolic flux response to support NADPH homeostasis, providing a rationale for the complex feedback regulation pattern at work.
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spelling pubmed-101462142023-04-29 Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis Pfeuty, Benjamin Hurbain, Julien Thommen, Quentin Metabolites Article Complex feedback regulation patterns shape the cellular metabolic response to external or internal perturbations. We propose here a framework consisting of a sampling-based metabolic control analysis of kinetic models to investigate the modes of regulatory interplay in metabolic functions. NADPH homeostasis, for instance in a context of oxidative stress, is an example of metabolic function that involves multiple feedback regulations which raises the issue of their concerted action. Our computational framework allows us to characterize both respective and combined effects of regulations, distinguishing between synergistic versus complementary modes of regulatory crosstalk. Synergistic regulation of G6PD enzymes and PGI enzymes is mediated by congruent effects between concentration sensitivities and reaction elasticities. Complementary regulation of pentose phosphate pathway and lower glycolysis relates to metabolic state-dependent range of regulation efficiency. These cooperative effects are shown to significantly improve metabolic flux response to support NADPH homeostasis, providing a rationale for the complex feedback regulation pattern at work. MDPI 2023-03-28 /pmc/articles/PMC10146214/ /pubmed/37110144 http://dx.doi.org/10.3390/metabo13040485 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pfeuty, Benjamin
Hurbain, Julien
Thommen, Quentin
Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title_full Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title_fullStr Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title_full_unstemmed Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title_short Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis
title_sort control analysis of cooperativity and complementarity in metabolic regulations: the case of nadph homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10146214/
https://www.ncbi.nlm.nih.gov/pubmed/37110144
http://dx.doi.org/10.3390/metabo13040485
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