title: Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus.
abstract: 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.
authors: Division of Molecular Biology, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria. dr.sabiha.yasmin@gmail.com
authors: Sabiha
authors: S
authors: Yasmin
authors: Laura
authors: L
authors: Alcazar-Fuoli
authors: Mario
authors: M
authors: Gründlinger
authors: Thomas
authors: T
authors: Puempel
authors: Timothy
authors: T
authors: Cairns
authors: Michael
authors: M
authors: Blatzer
authors: Jordi F
authors: JF
authors: Lopez
authors: Joan O
authors: JO
authors: Grimalt
authors: Elaine
authors: E
authors: Bignell
authors: Hubertus
authors: H
authors: Haas
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D001232:Aspergillus fumigatus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D018533:Biomass; D053898:Biosynthetic Pathways / Q000187:drug effects; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D004875:Ergosterol / Q000096:biosynthesis*; D005290:Ferric Compounds / Q000378:metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005800:Genes, Fungal / Q000235:genetics; D006877:Hydroxamic Acids / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D000090463:Iron Deficiencies; D008025:Ligases / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008826:Microbial Sensitivity Tests; D018384:Oxidative Stress / Q000187:drug effects; D055732:Pulmonary Aspergillosis / Q000382:microbiology; D011743:Pyrimidines / Q000494:pharmacology; D017262:Siderophores / Q000096:biosynthesis*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014774:Virulence / Q000187:drug effects / Q000235:genetics; D065819:Voriconazole
chemical_list: D005290:Ferric Compounds; D006877:Hydroxamic Acids; D011743:Pyrimidines; D017262:Siderophores; D014230:Triazoles; C053324:N,N',N''-triacetylfusarinine C; D000666:Amphotericin B; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D004746:Enoyl-CoA Hydratase; D008025:Ligases; D065819:Voriconazole; D008798:Mevalonic Acid; D004875:Ergosterol