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Caught before Released: Structural Mapping of the Reaction Trajectory for the Sofosbuvir Activating Enzyme, Human Histidine Triad Nucleotide Binding Protein 1 (hHint1)

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    Caught before Released: Structural Mapping of the Reaction Trajectory for the Sofosbuvir Activating Enzyme, Human Histidine Triad Nucleotide Binding Protein 1 (hHint1)
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    Department of Medicinal Chemistry University of Minnesota, Minneapolis, Minnesota 55455, United States
    *University of Minnesota, Department of Medicinal Chemistry, 2231 6th St. SE., 2-141 CCRB, Minneapolis, MN 55455. Phone: 612-625-2614. E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2017, 56, 28, 3559–3570
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    https://doi.org/10.1021/acs.biochem.7b00148
    Published June 22, 2017
    Copyright © 2017 American Chemical Society
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    Abstract

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    Human histidine triad nucleotide binding protein 1 (hHint1) is classified as an efficient nucleoside phosphoramidase and acyl-adenosine monophosphate hydrolase. Human Hint1 has been shown to be essential for the metabolic activation of nucleotide antiviral pronucleotides (i.e., proTides), such as the FDA approved hepatitis C drug, sofosbuvir. The active site of hHint1 comprises an ensemble of strictly conserved histidines, including nucleophilic His112. To structurally investigate the mechanism of hHint1 catalysis, we have designed and prepared nucleoside thiophosphoramidate substrates that are able to capture the transiently formed nucleotidylated-His112 intermediate (E*) using time-dependent crystallography. Utilizing a catalytically inactive hHint1 His112Asn enzyme variant and wild-type enzyme, the enzyme–substrate (ES1) and product (EP2) complexes were also cocrystallized, respectively, thus providing a structural map of the reaction trajectory. On the basis of these observations and the mechanistic necessity of proton transfers, proton inventory studies were carried out. Although we cannot completely exclude the possibility of more than one proton in flight, the results of these studies were consistent with the transfer of a single proton during the formation of the intermediate. Interestingly, structural analysis revealed that the critical proton transfers required for intermediate formation and hydrolysis may be mediated by a conserved active site water channel. Taken together, our results provide mechanistic insights underpinning histidine nucleophilic catalysis in general and hHint1 catalysis, in particular, thus aiding the design of future proTides and the elucidation of the natural function of the Hint family of enzymes.

    Copyright © 2017 American Chemical Society

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    This article is cited by 19 publications.

    1. Maxwell Dillenburg, Jacob Smith, Carston R. Wagner. The Many Faces of Histidine Triad Nucleotide Binding Protein 1 (HINT1). ACS Pharmacology & Translational Science 2023, 6 (10) , 1310-1322. https://doi.org/10.1021/acsptsci.3c00079
    2. Alexander Strom, Rachit Shah, Rafal Dolot, Melanie S. Rogers, Cher-Ling Tong, David Wang, Youlin Xia, John D. Lipscomb, Carston R. Wagner. Dynamic Long-Range Interactions Influence Substrate Binding and Catalysis by Human Histidine Triad Nucleotide-Binding Proteins (HINTs), Key Regulators of Multiple Cellular Processes and Activators of Antiviral ProTides. Biochemistry 2022, 61 (23) , 2648-2661. https://doi.org/10.1021/acs.biochem.2c00506
    3. Jiapeng Li, Shuhan Liu, Jian Shi, Xinwen Wang, Yanling Xue, Hao-Jie Zhu. Tissue-Specific Proteomics Analysis of Anti-COVID-19 Nucleoside and Nucleotide Prodrug-Activating Enzymes Provides Insights into the Optimization of Prodrug Design and Pharmacotherapy Strategy. ACS Pharmacology & Translational Science 2021, 4 (2) , 870-887. https://doi.org/10.1021/acsptsci.1c00016
    4. Alexander Strom, Rachit Shah, Carston R. Wagner. “Switching On” Enzyme Substrate Specificity Analysis with a Fluorescent Competitive Inhibitor. Biochemistry 2021, 60 (6) , 440-450. https://doi.org/10.1021/acs.biochem.0c00954
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    6. Harrison T. West, Clifford M. Csizmar, Carston R. Wagner. Tunable Supramolecular Assemblies from Amphiphilic Nucleoside Phosphoramidate Nanofibers by Enzyme Activation. Biomacromolecules 2018, 19 (7) , 2650-2656. https://doi.org/10.1021/acs.biomac.8b00254
    7. Blazej A. Wojtczak, Pawel J. Sikorski, Kaja Fac-Dabrowska, Anna Nowicka, Marcin Warminski, Dorota Kubacka, Elzbieta Nowak, Marcin Nowotny, Joanna Kowalska, Jacek Jemielity. 5′-Phosphorothiolate Dinucleotide Cap Analogues: Reagents for Messenger RNA Modification and Potent Small-Molecular Inhibitors of Decapping Enzymes. Journal of the American Chemical Society 2018, 140 (18) , 5987-5999. https://doi.org/10.1021/jacs.8b02597
    8. Kimberly M. Maize, Rachit Shah, Alex Strom, Sidath Kumarapperuma, Andrew Zhou, Carston R. Wagner, and Barry C. Finzel . A Crystal Structure Based Guide to the Design of Human Histidine Triad Nucleotide Binding Protein 1 (hHint1) Activated ProTides. Molecular Pharmaceutics 2017, 14 (11) , 3987-3997. https://doi.org/10.1021/acs.molpharmaceut.7b00664
    9. Aurélie Chazot, Claire Zimberger, Mikael Feracci, Adel Moussa, Steven Good, Jean-Pierre Sommadossi, Karine Alvarez, François Ferron, Bruno Canard, . The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution. PLOS Biology 2024, 22 (8) , e3002743. https://doi.org/10.1371/journal.pbio.3002743
    10. Silvia Amor-Barris, Tamas Lazar, Kristien Peeters, Shoshana J. Wodak, Albena Jordanova. In-depth characterization of HINT1 pathogenic variants. 2023https://doi.org/10.1101/2023.12.01.569336
    11. Béatrice Roy, Valentin Navarro, Suzanne Peyrottes. Prodrugs of Nucleoside 5'-Monophosphate Analogues: Overview of the Recent Literature Concerning their Synthesis and Applications. Current Medicinal Chemistry 2023, 30 (11) , 1256-1303. https://doi.org/10.2174/0929867329666220909122820
    12. Saumya Kapoor, Gurudutt Dubey, Samima Khatun, Prasad V. Bharatam. Remdesivir: Mechanism of Metabolic Conversion from Prodrug to Drug. Current Drug Metabolism 2022, 23 (1) , 73-81. https://doi.org/10.2174/1389200223666211228160314
    13. Rafał Dolot, Agnieszka Krakowiak, Renata Kaczmarek, Artur Włodarczyk, Marta Pichlak, Barbara Nawrot. Biochemical, crystallographic and biophysical characterization of histidine triad nucleotide-binding protein 2 with different ligands including a non-hydrolyzable analog of Ap4A. Biochimica et Biophysica Acta (BBA) - General Subjects 2021, 1865 (11) , 129968. https://doi.org/10.1016/j.bbagen.2021.129968
    14. Xiao-huan Liu, Xiao Zhang, Zhen-hua Lu, You-shuang Zhu, Tao Wang. Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection. Biomedicine & Pharmacotherapy 2021, 133 , 111035. https://doi.org/10.1016/j.biopha.2020.111035
    15. Katherine E. Squires, Douglas L. Mayers, Gregory R. Bluemling, Alexander A. Kolykhalov, David B. Guthrie, Prabhakar Reddy, Debbie G. Mitchell, Manohar T. Saindane, Zachary M. Sticher, Vindhya Edpuganti, Abel De La Rosa. ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens. Antimicrobial Agents and Chemotherapy 2020, 64 (9) https://doi.org/10.1128/AAC.00836-20
    16. Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I. Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley, . Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics. mBio 2020, 11 (2) https://doi.org/10.1128/mBio.00497-20
    17. Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I. Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley. Histidine-Triad Hydrolases Provide Resistance to Peptide-Nucleotide Antibiotics. 2020https://doi.org/10.1101/2020.03.04.977132
    18. Rachit M. Shah, Kimberly M. Maize, Harrison T. West, Alexander M. Strom, Barry C. Finzel, Carston R. Wagner. Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia. Journal of Molecular Biology 2018, 430 (17) , 2709-2721. https://doi.org/10.1016/j.jmb.2018.05.028
    19. Cyril B Dousson. Current and future use of nucleo(s)tide prodrugs in the treatment of hepatitis C virus infection. Antiviral Chemistry and Chemotherapy 2018, 26 https://doi.org/10.1177/2040206618756430
    20. Magdalena Slusarczyk, Michaela Serpi, Fabrizio Pertusati. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antiviral Chemistry and Chemotherapy 2018, 26 https://doi.org/10.1177/2040206618775243
    21. Guangchao Liang, Charles Edwin Webster. Phosphoramidate hydrolysis catalyzed by human histidine triad nucleotide binding protein 1 (hHint1): a cluster-model DFT computational study. Org. Biomol. Chem. 2017, 15 (40) , 8661-8668. https://doi.org/10.1039/C7OB02098H
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    Biochemistry

    Cite this: Biochemistry 2017, 56, 28, 3559–3570
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.7b00148
    Published June 22, 2017
    Copyright © 2017 American Chemical Society
    Request reuse permissions

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