| Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. | |
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MedLine Citation:
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PMID: 20439709 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mycobacterium tuberculosis (Mtb). In vitro, Mtb is able to grow on a variety of carbon sources, but mounting evidence has implicated fatty acids as the major source of carbon and energy for Mtb during infection. When bacterial metabolism is primarily fueled by fatty acids, biosynthesis of sugars from intermediates of the tricarboxylic acid cycle is essential for growth. The role of gluconeogenesis in the pathogenesis of Mtb however remains unaddressed. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the first committed step of gluconeogenesis. We applied genetic analyses and (13)C carbon tracing to confirm that PEPCK is essential for growth of Mtb on fatty acids and catalyzes carbon flow from tricarboxylic acid cycle-derived metabolites to gluconeogenic intermediates. We further show that PEPCK is required for growth of Mtb in isolated bone marrow-derived murine macrophages and in mice. Importantly, Mtb lacking PEPCK not only failed to replicate in mouse lungs but also failed to survive, and PEPCK depletion during the chronic phase of infection resulted in mycobacterial clearance. Mtb thus relies on gluconeogenesis throughout the infection. PEPCK depletion also attenuated Mtb in IFNgamma-deficient mice, suggesting that this enzyme represents an attractive target for chemotherapy. |
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Authors:
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Joeli Marrero; Kyu Y Rhee; Dirk Schnappinger; Kevin Pethe; Sabine Ehrt |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-05-03 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-26 Completed Date: 2010-06-29 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 9819-24 Citation Subset: IM |
Affiliation:
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Department of Microbiology and Immunology and Department of Medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York, NY 10065, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carbon / metabolism* Citric Acid Cycle* Fatty Acids / metabolism Gluconeogenesis* Macrophages / microbiology Mice Mice, Inbred C57BL Mycobacterium tuberculosis / genetics, growth & development, metabolism* Phosphoenolpyruvate Carboxykinase (GTP) / genetics, metabolism Tuberculosis / microbiology* Virus Replication |
| Grant Support | |
ID/Acronym/Agency:
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R01AI63446/AI/NIAID NIH HHS; R01AI63446-03S1/AI/NIAID NIH HHS; T32AI007621/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 7440-44-0/Carbon; EC 4.1.1.32/Phosphoenolpyruvate Carboxykinase (GTP) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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