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An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism

Methionine (Met) is an essential amino acid that is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent. Methionine used for AdoMet synthesis can be replenished via remethylation of homocysteine. Alternatively, homocysteine can be converted to cysteine v...

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Autores principales: Korendyaseva, Tatyana K., Kuvatov, Denis N., Volkov, Vladimir A., Martinov, Michael V., Vitvitsky, Victor M., Banerjee, Ruma, Ataullakhanov, Fazoil I.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346559/
https://www.ncbi.nlm.nih.gov/pubmed/18451990
http://dx.doi.org/10.1371/journal.pcbi.1000076
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author Korendyaseva, Tatyana K.
Kuvatov, Denis N.
Volkov, Vladimir A.
Martinov, Michael V.
Vitvitsky, Victor M.
Banerjee, Ruma
Ataullakhanov, Fazoil I.
author_facet Korendyaseva, Tatyana K.
Kuvatov, Denis N.
Volkov, Vladimir A.
Martinov, Michael V.
Vitvitsky, Victor M.
Banerjee, Ruma
Ataullakhanov, Fazoil I.
author_sort Korendyaseva, Tatyana K.
collection PubMed
description Methionine (Met) is an essential amino acid that is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent. Methionine used for AdoMet synthesis can be replenished via remethylation of homocysteine. Alternatively, homocysteine can be converted to cysteine via the transsulfuration pathway. Aberrations in methionine metabolism are associated with a number of complex diseases, including cancer, anemia, and neurodegenerative diseases. The concentration of methionine in blood and in organs is tightly regulated. Liver plays a key role in buffering blood methionine levels, and an interesting feature of its metabolism is that parallel tracks exist for the synthesis and utilization of AdoMet. To elucidate the molecular mechanism that controls metabolic fluxes in liver methionine metabolism, we have studied the dependencies of AdoMet concentration and methionine consumption rate on methionine concentration in native murine hepatocytes at physiologically relevant concentrations (40–400 µM). We find that both [AdoMet] and methionine consumption rates do not change gradually with an increase in [Met] but rise sharply (∼10-fold) in the narrow Met interval from 50 to 100 µM. Analysis of our experimental data using a mathematical model reveals that the sharp increase in [AdoMet] and the methionine consumption rate observed within the trigger zone are associated with metabolic switching from methionine conservation to disposal, regulated allosterically by switching between parallel pathways. This regulatory switch is triggered by [Met] and provides a mechanism for stabilization of methionine levels in blood over wide variations in dietary methionine intake.
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spelling pubmed-23465592008-05-02 An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism Korendyaseva, Tatyana K. Kuvatov, Denis N. Volkov, Vladimir A. Martinov, Michael V. Vitvitsky, Victor M. Banerjee, Ruma Ataullakhanov, Fazoil I. PLoS Comput Biol Research Article Methionine (Met) is an essential amino acid that is needed for the synthesis of S-adenosylmethionine (AdoMet), the major biological methylating agent. Methionine used for AdoMet synthesis can be replenished via remethylation of homocysteine. Alternatively, homocysteine can be converted to cysteine via the transsulfuration pathway. Aberrations in methionine metabolism are associated with a number of complex diseases, including cancer, anemia, and neurodegenerative diseases. The concentration of methionine in blood and in organs is tightly regulated. Liver plays a key role in buffering blood methionine levels, and an interesting feature of its metabolism is that parallel tracks exist for the synthesis and utilization of AdoMet. To elucidate the molecular mechanism that controls metabolic fluxes in liver methionine metabolism, we have studied the dependencies of AdoMet concentration and methionine consumption rate on methionine concentration in native murine hepatocytes at physiologically relevant concentrations (40–400 µM). We find that both [AdoMet] and methionine consumption rates do not change gradually with an increase in [Met] but rise sharply (∼10-fold) in the narrow Met interval from 50 to 100 µM. Analysis of our experimental data using a mathematical model reveals that the sharp increase in [AdoMet] and the methionine consumption rate observed within the trigger zone are associated with metabolic switching from methionine conservation to disposal, regulated allosterically by switching between parallel pathways. This regulatory switch is triggered by [Met] and provides a mechanism for stabilization of methionine levels in blood over wide variations in dietary methionine intake. Public Library of Science 2008-05-02 /pmc/articles/PMC2346559/ /pubmed/18451990 http://dx.doi.org/10.1371/journal.pcbi.1000076 Text en Korendyaseva et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Korendyaseva, Tatyana K.
Kuvatov, Denis N.
Volkov, Vladimir A.
Martinov, Michael V.
Vitvitsky, Victor M.
Banerjee, Ruma
Ataullakhanov, Fazoil I.
An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title_full An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title_fullStr An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title_full_unstemmed An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title_short An Allosteric Mechanism for Switching between Parallel Tracks in Mammalian Sulfur Metabolism
title_sort allosteric mechanism for switching between parallel tracks in mammalian sulfur metabolism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346559/
https://www.ncbi.nlm.nih.gov/pubmed/18451990
http://dx.doi.org/10.1371/journal.pcbi.1000076
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