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The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization
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Alam, Mohammad T., Olin-Sandoval, Viridiana, Stincone, Anna, Keller, Markus A., Zelezniak, Aleksej, Luisi, Ben and Ralser, Markus (2017) The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization. Nature Communications, 8 . 16018. doi:10.1038/ncomms16018 ISSN 2041-1723.
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Official URL: https://doi.org/10.1038/ncomms16018
Abstract
Metabolites can inhibit the enzymes that generate them. To explore the general nature of metabolic self-inhibition, we surveyed enzymological data accrued from a century of experimentation and generated a genome-scale enzyme-inhibition network. Enzyme inhibition is often driven by essential metabolites, affects the majority of biochemical processes, and is executed by a structured network whose topological organization is reflecting chemical similarities that exist between metabolites. Most inhibitory interactions are competitive, emerge in the close neighbourhood of the inhibited enzymes, and result from structural similarities between substrate and inhibitors. Structural constraints also explain one-third of allosteric inhibitors, a finding rationalized by crystallographic analysis of allosterically inhibited L-lactate dehydrogenase. Our findings suggest that the primary cause of metabolic enzyme inhibition is not the evolution of regulatory metabolite–enzyme interactions, but a finite structural diversity prevalent within the metabolome. In eukaryotes, compartmentalization minimizes inevitable enzyme inhibition and alleviates constraints that self-inhibition places on metabolism.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QP Physiology | ||||||||||||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Metabolites, Enzymes, Metabolism | ||||||||||||||||||||||||||||||
| Journal or Publication Title: | Nature Communications | ||||||||||||||||||||||||||||||
| Publisher: | Nature Publishing Group | ||||||||||||||||||||||||||||||
| ISSN: | 2041-1723 | ||||||||||||||||||||||||||||||
| Official Date: | 10 July 2017 | ||||||||||||||||||||||||||||||
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| Volume: | 8 | ||||||||||||||||||||||||||||||
| Article Number: | 16018 | ||||||||||||||||||||||||||||||
| DOI: | 10.1038/ncomms16018 | ||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 10 July 2017 | ||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 11 July 2017 | ||||||||||||||||||||||||||||||
| Funder: | Cancer Research UK (CRUK), Medical Research Council (Great Britain) (MRC), Wellcome Trust (London, England), European Research Council (ERC), Consejo nacional de ciencia y tecnología (México), European Molecular Biology Organization (EMBO), European Commission (EC), Marie Skłodowska-Curie Actions, Fonds zur Förderung der Wissenschaftlichen Forschung (Austria) (FWF) | ||||||||||||||||||||||||||||||
| Grant number: | FC001134 (CRUK), FC001134 (MRC), FC001134, 093735/Z/10/Z (Wellcome Trust (London, England)), Stg 260809 (ERC), 232510 (Consejo nacional de ciencia y tecnología (México)), ALTF-969 2014 (EMBO), TFCOFUND2013, GA-2013-609409 (EC), J3341 (FWF) | ||||||||||||||||||||||||||||||
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