Pathway thermodynamics highlights kinetic obstacles in central metabolism.

In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of react...

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Autores principales:	Elad Noor, Arren Bar-Even, Avi Flamholz, Ed Reznik, Wolfram Liebermeister, Ron Milo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c82b19fb103d429d92d566fddf014399
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spelling	oai:doaj.org-article:c82b19fb103d429d92d566fddf0143992021-11-18T05:53:08ZPathway thermodynamics highlights kinetic obstacles in central metabolism.1553-734X1553-735810.1371/journal.pcbi.1003483https://doaj.org/article/c82b19fb103d429d92d566fddf0143992014-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24586134/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG'). Accordingly, if an enzyme catalyzes a reaction with a ΔrG' of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG' approaches equilibrium (ΔrG' = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the thermodynamic and kinetic quality of different pathway chemistries that produce the same molecules.Elad NoorArren Bar-EvenAvi FlamholzEd ReznikWolfram LiebermeisterRon MiloPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 2, p e1003483 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Elad Noor Arren Bar-Even Avi Flamholz Ed Reznik Wolfram Liebermeister Ron Milo Pathway thermodynamics highlights kinetic obstacles in central metabolism.
description	In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG'). Accordingly, if an enzyme catalyzes a reaction with a ΔrG' of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG' approaches equilibrium (ΔrG' = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the thermodynamic and kinetic quality of different pathway chemistries that produce the same molecules.
format	article
author	Elad Noor Arren Bar-Even Avi Flamholz Ed Reznik Wolfram Liebermeister Ron Milo
author_facet	Elad Noor Arren Bar-Even Avi Flamholz Ed Reznik Wolfram Liebermeister Ron Milo
author_sort	Elad Noor
title	Pathway thermodynamics highlights kinetic obstacles in central metabolism.
title_short	Pathway thermodynamics highlights kinetic obstacles in central metabolism.
title_full	Pathway thermodynamics highlights kinetic obstacles in central metabolism.
title_fullStr	Pathway thermodynamics highlights kinetic obstacles in central metabolism.
title_full_unstemmed	Pathway thermodynamics highlights kinetic obstacles in central metabolism.
title_sort	pathway thermodynamics highlights kinetic obstacles in central metabolism.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/c82b19fb103d429d92d566fddf014399
work_keys_str_mv	AT eladnoor pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism AT arrenbareven pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism AT aviflamholz pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism AT edreznik pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism AT wolframliebermeister pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism AT ronmilo pathwaythermodynamicshighlightskineticobstaclesincentralmetabolism
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Pathway thermodynamics highlights kinetic obstacles in central metabolism.

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