Abstract

Phosphoribosyl pyrophosphate (PRPP) is a key intermediate in the biosynthesis of purine and pyrimidine nucleotides, histidine, tryptophan, and cofactors NAD and NADP. Abnormal regulation of PRPP synthase (PRPS) is associated with human disorders, including Arts syndrome, retinal dystrophy and gouty arthritis. Recent studies have demonstrated that PRPS can form filamentous cytoophidia in eukaryotes. Here we show that PRPS forms cytoophidia in prokaryotes both in vitro and in vivo. Moreover, we solve two distinct filament structures of E. coli PRPS at near-atomic resolution under Cryo-EM. The formation of the two types of filaments is controlled by the binding of different ligands. One filament type is resistant to allosteric inhibition. The structural comparison reveals conformational changes of a regulatory flexible loop, which may regulate the binding of the allosteric inhibitor and the substrate ATP. A noncanonical allosteric AMP/ADP binding site is identified to stabilize the conformation of the regulatory flexible loop. Our findings not only explore a new mechanism of PRPS regulation with structural basis, but also propose an additional layer of cell metabolism through PRPS filamentation.

Data availability

Atomic models generated in this study have been deposited at thePDB under the accession codes 7XMU, 7XMV, 7XN3. Cryo-EMmaps deposited to EMDB as: EMD-33305, EMD-33306, EMD-33309.

The following data sets were generated

Article and author information

Author details

  1. Huanhuan Hu

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5997-530X
  2. Guangming Lu

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Chia-Chun Chang

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yilan Li

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jiale Zhong

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5873-0450
  6. Chen-Jun Guo

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xian Zhou

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Boqi Yin

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Tianyi Zhang

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4632-6298
  10. Ji-Long Liu

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    For correspondence
    liujl3@shanghaitech.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4834-8554

Funding

Ministry of Science and Technology of the People's Republic of China (2021YFA0804701-4)

  • Ji-Long Liu

National Natural Science Foundation of China (31771490)

  • Ji-Long Liu

Shanghai Science and Technology Commission (20JC1410500)

  • Ji-Long Liu

Medical Research Council (MC_UU_12021/3; MC_U137788471)

  • Ji-Long Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward H Egelman, University of Virginia, United States

Publication history

  1. Received: April 18, 2022
  2. Preprint posted: April 28, 2022 (view preprint)
  3. Accepted: June 10, 2022
  4. Accepted Manuscript published: June 23, 2022 (version 1)
  5. Version of Record published: June 24, 2022 (version 2)

Copyright

© 2022, Hu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Huanhuan Hu
  2. Guangming Lu
  3. Chia-Chun Chang
  4. Yilan Li
  5. Jiale Zhong
  6. Chen-Jun Guo
  7. Xian Zhou
  8. Boqi Yin
  9. Tianyi Zhang
  10. Ji-Long Liu
(2022)
Filamentation modulates allosteric regulation of PRPS
eLife 11:e79552.
https://doi.org/10.7554/eLife.79552

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