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Title: Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity

Abstract

Inosine 5´-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH ( CpIMPDH) in complex with inosine 5´-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO 2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.

Authors:
 [1];  [2];  [3];  [3];  [4];  [1];  [5]
  1. Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; Argonne National Laboratory, Argonne, IL (United States). Structural Biology Center.
  2. Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases.
  3. Brandeis Univ., Waltham, MA (United States). Dept. of Biology.
  4. Univ. of Houston, Houston, TX (United States). Dept. of Pharmacological and Pharmaceutical Sciences.
  5. Brandeis Univ., Waltham, MA (United States). Depts. of Biology and Chemistry.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID)
OSTI Identifier:
1212708
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Acta Crystallographica. Section F, Structural Biology Communications
Additional Journal Information:
Journal Volume: 71; Journal Issue: 5; Journal ID: ISSN 2053-230X
Publisher:
International Union of Crystallography
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Cryptosporidium; inosine 5′-monophosphate dehydrogenase; P131

Citation Formats

Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, and Hedstrom, Lizbeth. Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity. United States: N. p., 2015. Web. doi:10.1107/S2053230X15000187.
Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, & Hedstrom, Lizbeth. Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity. United States. doi:10.1107/S2053230X15000187.
Kim, Youngchang, Makowska-Grzyska, Magdalena, Gorla, Suresh Kumar, Gollapalli, Deviprasad R., Cuny, Gregory D., Joachimiak, Andrzej, and Hedstrom, Lizbeth. 2015. "Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity". United States. doi:10.1107/S2053230X15000187. https://www.osti.gov/servlets/purl/1212708.
@article{osti_1212708,
title = {Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity},
author = {Kim, Youngchang and Makowska-Grzyska, Magdalena and Gorla, Suresh Kumar and Gollapalli, Deviprasad R. and Cuny, Gregory D. and Joachimiak, Andrzej and Hedstrom, Lizbeth},
abstractNote = {Inosine 5´-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 5´-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.},
doi = {10.1107/S2053230X15000187},
journal = {Acta Crystallographica. Section F, Structural Biology Communications},
number = 5,
volume = 71,
place = {United States},
year = 2015,
month = 4
}

Journal Article:
Free Publicly Available Full Text
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Citation Metrics:
Cited by: 4works
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  • Inosine 5'-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment ofCryptosporidiuminfections. Here, the structure ofC. parvumIMPDH (CpIMPDH) in complex with inosine 5'-monophosphate (IMP) and P131, an inhibitor within vivoanticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO 2moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization ofC. parvuminhibitorsmore » for both antiparasitic and antibacterial applications.« less
  • Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5{prime}-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10{sup 3} selectivity for the parasite enzyme over human IMPDH2.
  • Human inosine 5′-monophosphate dehydrogenase (hIMPDH) is a rate-limiting enzyme in the de novo biosynthetic pathway of purine nucleotides, playing crucial roles in cellular proliferation, differentiation, and transformation. Dysregulation of hIMPDH expression and activity have been found in a variety of human cancers including leukemia. In this study, we found that myricetin, a naturally occurring phytochemical existed in berries, wine and tea, was a novel inhibitor of human type 1 and type 2 IMPDH (hIMPDH1/2) with IC{sub 50} values of 6.98 ± 0.22 μM and 4.10 ± 0.14 μM, respectively. Enzyme kinetic analysis using Lineweaver-Burk plot revealed that myricetin is a mix-type inhibitor for hIMPDH1/2. Differential scanningmore » fluorimetry and molecular docking simulation data demonstrate that myricetin is capable of binding with hIMPDH1/2. Myricetin treatment exerts potent anti-proliferative and pro-apoptotic effects on K562 human leukemia cells in a dose-dependent manner. Importantly, cytotoxicity of myricetin on K562 cells were markedly attenuated by exogenous addition of guanosine, a salvage pathway of maintaining intracellular pool of guanine nucleotides. Taking together, these results indicate that natural product myricetin exhibits potent anti-leukemia activity by interfering with purine nucleotides biosynthetic pathway through the suppression of hIMPDH1/2 catalytic activity. - Highlights: • Myricetin, a common dietary flavonoid, is a novel inhibitor of hIMPDH1/2. • Myricetin directly binds with hIMPDH1/2 and induces cell cycle arrest and apoptosis of leukemia cells. • The cytotoxicity of myricetin on K562 cells is markedly attenuated by exogenous addition of guanosine.« less