| Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus. | |
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MedLine Citation:
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PMID: 22106303 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants. |
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Authors:
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Sabiha Yasmin; Laura Alcazar-Fuoli; Mario Gründlinger; Thomas Puempel; Timothy Cairns; Michael Blatzer; Jordi F Lopez; Joan O Grimalt; Elaine Bignell; Hubertus Haas |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-11-21 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-22 Completed Date: 2012-04-12 Revised Date: 2013-05-23 |
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: E497-504 Citation Subset: IM |
Affiliation:
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Division of Molecular Biology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria. dr.sabiha.yasmin@gmail.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amphotericin B
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pharmacology Animals Aspergillus fumigatus / enzymology, genetics, metabolism*, pathogenicity Biomass Biosynthetic Pathways / drug effects Enoyl-CoA Hydratase / metabolism Ergosterol / biosynthesis* Ferric Compounds / metabolism Gene Deletion Gene Expression Regulation, Enzymologic / drug effects Gene Expression Regulation, Fungal / drug effects Gene Silencing / drug effects Genes, Fungal / genetics Hydroxamic Acids / metabolism Hydroxymethylglutaryl CoA Reductases / genetics, metabolism Iron / deficiency Ligases / metabolism Lovastatin / pharmacology Mevalonic Acid / metabolism* Mice Microbial Sensitivity Tests Oxidative Stress / drug effects Pulmonary Aspergillosis / microbiology Pyrimidines / pharmacology Siderophores / biosynthesis* Triazoles / pharmacology Up-Regulation / drug effects Virulence / drug effects, genetics |
| Grant Support | |
ID/Acronym/Agency:
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P 18606-B11//Austrian Science Fund FWF; P 21643-B11//Austrian Science Fund FWF |
| Chemical | |
Reg. No./Substance:
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0/Ferric Compounds; 0/Hydroxamic Acids; 0/Pyrimidines; 0/Siderophores; 0/Triazoles; 0/voriconazole; 1397-89-3/Amphotericin B; 150-97-0/Mevalonic Acid; 57-87-4/Ergosterol; 59200-35-0/N,N',N''-triacetylfusarinine C; 7439-89-6/Iron; 75330-75-5/Lovastatin; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 4.2.1.17/Enoyl-CoA Hydratase; EC 6.-/Ligases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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