IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v6y2015i1d10.1038_ncomms9923.html
   My bibliography  Save this article

Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases

Author

Listed:
  • Rubén M. Buey

    (Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain)

  • Rodrigo Ledesma-Amaro

    (Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain)

  • Adrián Velázquez-Campoy

    (Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit IQFR-CSIC-BIFI, Universidad de Zaragoza, C/Mariano Esquillor, Zaragoza 50018, Spain
    University of Zaragoza
    Instituto de Investigaciones Sanitarias de Aragón (IIS-A)
    Fundación ARAID, Government of Aragón)

  • Mónica Balsera

    (Instituto de Recursos Naturales y Agrobiología (IRNASA-CSIC))

  • Mónica Chagoyen

    (Computational Systems Biology Group, Centro Nacional de Biotecnología (CNB-CSIC))

  • José M. de Pereda

    (Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca), Campus Miguel de Unamuno, Salamanca 37007, Spain)

  • José L. Revuelta

    (Metabolic Engineering Group, Dpto. Microbiología y Genética. Universidad de Salamanca, Campus Miguel de Unamuno, Edificio Departamental, Salamanca 37007, Spain)

Abstract

Inosine-5′-monophosphate dehydrogenase (IMPDH) plays key roles in purine nucleotide metabolism and cell proliferation. Although IMPDH is a widely studied therapeutic target, there is limited information about its physiological regulation. Using Ashbya gossypii as a model, we describe the molecular mechanism and the structural basis for the allosteric regulation of IMPDH by guanine nucleotides. We report that GTP and GDP bind to the regulatory Bateman domain, inducing octamers with compromised catalytic activity. Our data suggest that eukaryotic and prokaryotic IMPDHs might have developed different regulatory mechanisms, with GTP/GDP inhibiting only eukaryotic IMPDHs. Interestingly, mutations associated with human retinopathies map into the guanine nucleotide-binding sites including a previously undescribed non-canonical site and disrupt allosteric inhibition. Together, our results shed light on the mechanisms of the allosteric regulation of enzymes mediated by Bateman domains and provide a molecular basis for certain retinopathies, opening the door to new therapeutic approaches.

Suggested Citation

  • Rubén M. Buey & Rodrigo Ledesma-Amaro & Adrián Velázquez-Campoy & Mónica Balsera & Mónica Chagoyen & José M. de Pereda & José L. Revuelta, 2015. "Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases," Nature Communications, Nature, vol. 6(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9923
    DOI: 10.1038/ncomms9923
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms9923
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/ncomms9923?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Chuan Qin & Leonie G. Graf & Kilian Striska & Markus Janetzky & Norman Geist & Robin Specht & Sabrina Schulze & Gottfried J. Palm & Britta Girbardt & Babett Dörre & Leona Berndt & Stefan Kemnitz & Mar, 2024. "Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Ondřej Bulvas & Zdeněk Knejzlík & Jakub Sýs & Anatolij Filimoněnko & Monika Čížková & Kamila Clarová & Dominik Rejman & Tomáš Kouba & Iva Pichová, 2024. "Deciphering the allosteric regulation of mycobacterial inosine-5′-monophosphate dehydrogenase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9923. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.