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Role of HSP90 in the Regulation of de Novo Purine Biosynthesis

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    Role of HSP90 in the Regulation of de Novo Purine Biosynthesis
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    • Anthony M. Pedley
      Anthony M. Pedley
      Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
      More by Anthony M. Pedley
      Orcidhttp://orcid.org/0000-0003-1034-5072
    • Georgios I. Karras
      Georgios I. Karras
      Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, United States
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    • Xin Zhang
      Xin Zhang
      Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
      More by Xin Zhang
      Orcidhttp://orcid.org/0000-0001-6686-1645
    • Susan Lindquist
      Susan Lindquist
      Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, United States
      Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, United States
      Howard Hughes Medical Institute, Cambridge, Massachusetts 02142, United States
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    • Stephen J. Benkovic*
      Stephen J. Benkovic
      Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
      *Address: 414 Wartik Laboratory, The Pennsylvania State University, University Park, PA 16802. E-mail: [email protected]
      More by Stephen J. Benkovic
      Orcidhttp://orcid.org/0000-0003-3680-3481
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    Biochemistry

    Cite this: Biochemistry 2018, 57, 23, 3217–3221
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    https://doi.org/10.1021/acs.biochem.8b00140
    Published March 19, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    Despite purines making up one of the largest classes of metabolites in a cell, little is known about the regulatory mechanisms that facilitate efficient purine production. Under conditions resulting in high purine demand, enzymes within the de novo purine biosynthetic pathway cluster into multienzyme assemblies called purinosomes. Purinosome formation has been linked to molecular chaperones HSP70 and HSP90; however, the involvement of these molecular chaperones in purinosome formation remains largely unknown. Here, we present a new-found biochemical mechanism for the regulation of de novo purine biosynthetic enzymes mediated through HSP90. HSP90–client protein interaction assays were employed to identify two enzymes within the de novo purine biosynthetic pathway, PPAT and FGAMS, as client proteins of HSP90. Inhibition of HSP90 by STA9090 abrogated these interactions and resulted in a decrease in the level of available soluble client protein while having no significant effect on their interactions with HSP70. These findings provide a mechanism to explain the dependence of purinosome assembly on HSP90 activity. The combined efforts of molecular chaperones in the maturation of PPAT and FGAMS result in purinosome formation and are likely essential for enhancing the rate of purine production to meet intracellular purine demand.

    Copyright © 2018 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.8b00140.

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    Cited By

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    This article is cited by 18 publications.

    1. Chunliang Liu, Giselle M. Knudsen, Anthony M. Pedley, Jingxuan He, Jared L. Johnson, Tomer M. Yaron, Lewis C. Cantley, Stephen J. Benkovic. Mapping Post-Translational Modifications of de Novo Purine Biosynthetic Enzymes: Implications for Pathway Regulation. Journal of Proteome Research 2019, 18 (5) , 2078-2087. https://doi.org/10.1021/acs.jproteome.8b00969
    2. Di Wu, Shengqiang Yang, Chenyang Yuan, Kejia Zhang, Jiachen Tan, Kaifeng Guan, Hong Zeng, Chunjie Huang. Targeting purine metabolism-related enzymes for therapeutic intervention: A review from molecular mechanism to therapeutic breakthrough. International Journal of Biological Macromolecules 2024, 282 , 136828. https://doi.org/10.1016/j.ijbiomac.2024.136828
    3. Seiya Yamada, Tomoya Mizukoshi, Ayaka Sato, Shin-ichi Sakakibara. Purinosomes and Purine Metabolism in Mammalian Neural Development: A Review. ACTA HISTOCHEMICA ET CYTOCHEMICA 2024, 57 (3) , 89-100. https://doi.org/10.1267/ahc.24-00027
    4. Simone Allegrini, Marcella Camici, Mercedes Garcia-Gil, Rossana Pesi, Maria Grazia Tozzi. Interplay between mTOR and Purine Metabolism Enzymes and Its Relevant Role in Cancer. International Journal of Molecular Sciences 2024, 25 (12) , 6735. https://doi.org/10.3390/ijms25126735
    5. Jared A. M. Bard, D. Allan Drummond. Chaperone regulation of biomolecular condensates. Frontiers in Biophysics 2024, 2 https://doi.org/10.3389/frbis.2024.1342506
    6. Matthew J. Binder, Anthony M. Pedley. The roles of molecular chaperones in regulating cell metabolism. FEBS Letters 2023, 597 (13) , 1681-1701. https://doi.org/10.1002/1873-3468.14682
    7. Sukhwinder Singh, Ruchi Anand. Diverse strategies adopted by nature for regulating purine biosynthesis via fine-tuning of purine metabolic enzymes. Current Opinion in Chemical Biology 2023, 73 , 102261. https://doi.org/10.1016/j.cbpa.2022.102261
    8. Alexsandra S. Zelentsova, Alexei V. Deykin, Vladislav O. Soldatov, Anastasia A. Ulezko, Alina Y. Borisova, Veronika S. Belyaeva, Marina Y. Skorkina, Plamena R. Angelova. P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases. eneuro 2022, 9 (6) , ENEURO.0092-22.2022. https://doi.org/10.1523/ENEURO.0092-22.2022
    9. Anthony M. Pedley, Vidhi Pareek, Stephen J. Benkovic. The Purinosome: A Case Study for a Mammalian Metabolon. Annual Review of Biochemistry 2022, 91 (1) , 89-106. https://doi.org/10.1146/annurev-biochem-032620-105728
    10. Anthony M. Pedley, Jack P. Boylan, Chung Yu Chan, Erin L. Kennedy, Minjoung Kyoung, Stephen J. Benkovic. Purine biosynthetic enzymes assemble into liquid-like condensates dependent on the activity of chaperone protein HSP90. Journal of Biological Chemistry 2022, 298 (5) , 101845. https://doi.org/10.1016/j.jbc.2022.101845
    11. Kyle L. Fulghum, Timothy N. Audam, Pawel K. Lorkiewicz, Yuting Zheng, Michael Merchant, Timothy D. Cummins, William L. Dean, Teresa A. Cassel, Teresa W.M. Fan, Bradford G. Hill. In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium. Journal of Molecular and Cellular Cardiology 2022, 162 , 32-42. https://doi.org/10.1016/j.yjmcc.2021.08.013
    12. M. Nieves Calvo-Vidal, Nahuel Zamponi, Jan Krumsiek, Max A. Stockslager, Maria V. Revuelta, Jude M. Phillip, Rossella Marullo, Ekaterina Tikhonova, Nikita Kotlov, Jayeshkumar Patel, Shao Ning Yang, Lucy Yang, Tony Taldone, Catherine Thieblemont, John P. Leonard, Peter Martin, Giorgio Inghirami, Gabriela Chiosis, Scott R. Manalis, Leandro Cerchietti. Oncogenic HSP90 Facilitates Metabolic Alterations in Aggressive B-cell Lymphomas. Cancer Research 2021, 81 (20) , 5202-5216. https://doi.org/10.1158/0008-5472.CAN-21-2734
    13. Vidhi Pareek, Anthony M. Pedley, Stephen J. Benkovic. Human de novo purine biosynthesis. Critical Reviews in Biochemistry and Molecular Biology 2021, 56 (1) , 1-16. https://doi.org/10.1080/10409238.2020.1832438
    14. Cyrielle Doigneaux, Anthony M. Pedley, Ishna N. Mistry, Monika Papayova, Stephen J. Benkovic, Ali Tavassoli. Hypoxia drives the assembly of the multienzyme purinosome complex. Journal of Biological Chemistry 2020, 295 (28) , 9551-9566. https://doi.org/10.1074/jbc.RA119.012175
    15. Maximilian M. Biebl, Johannes Buchner. Structure, Function, and Regulation of the Hsp90 Machinery. Cold Spring Harbor Perspectives in Biology 2019, 11 (9) , a034017. https://doi.org/10.1101/cshperspect.a034017
    16. Yuanyuan Zheng, Xiaona Li, Xiangfeng Chen, Zongwei Cai, Hongzhi Zhao. Simultaneous determination of amino acids, purines and derivatives in serum by ultrahigh‐performance liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry 2019, 33 (1) , 81-88. https://doi.org/10.1002/rcm.8317
    17. Chung Yu Chan, Anthony M. Pedley, Doory Kim, Chenglong Xia, Xiaowei Zhuang, Stephen J. Benkovic. Microtubule-directed transport of purine metabolons drives their cytosolic transit to mitochondria. Proceedings of the National Academy of Sciences 2018, 115 (51) , 13009-13014. https://doi.org/10.1073/pnas.1814042115
    18. Jie Yin, Wenkai Ren, Xingguo Huang, Jinping Deng, Tiejun Li, Yulong Yin. Potential Mechanisms Connecting Purine Metabolism and Cancer Therapy. Frontiers in Immunology 2018, 9 https://doi.org/10.3389/fimmu.2018.01697
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    Biochemistry

    Cite this: Biochemistry 2018, 57, 23, 3217–3221
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.8b00140
    Published March 19, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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