User:Matthew Whiteside/Notebook/Fumigatus Microarray/2009/03/12

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Fumigatus Research

Metabolism Targets

Carbon metabolism

  1. possible players: glycogen phosphorylase (Afu1g12920), alcohol dehydrogenase (Afu3g01490), isoamyl alcohol oxidase (Afu3g07410) and NAD-dependent formate dehydrogenase (Afu6g04920).

GABA metabolism

  1. Afu5g00710 (GABA permease, putative)
    • upreg in our study, SreA, and StuA studies.
Nitrogen metabolism
  • AreA & B
    • main repressors in nitrogen repressing system (probably cooperate)
    • e.g. arginine use as N source requires agaA and otaA genes (arginase & ornithine aminotransferase), repressed when ammonium available.
  • PopB
    • deadenalyase (remove polyA tail = +mRNA decay)
    • AreA regulated by Gln (glutamine).
    • Many N metab genes are increased degraded in response to Gln by PopB
    • P-body (cytoplasmic structure) is site of action (mRNA degradation by signalling pathways).
TCA
  • GABA is catabolized to succinate via succinicsemialdehyde. potential bypass outside the classical tricarboxylic acid cycle

Iron Regulation

A. nidulans Hap complex
    • Heterotrimeric CCAATT-binding complex (CBC). Evo conserved complex of HapB, C & E.
    • A. nidulans has HapX. Repressed by GATA-factor SreA (iron regulation)
      • repressed during iron starvation.
    • Also CBC is modified by Thioredoxin A (trxA). HapC is oxidized by trxA. When reduced HapC locates to cytoplasm, and no transcription.
    • CBC is regulated by post-translation mech (trxA) and transcriptional mech (sreA) for tight control linked to iron.
A. fumigatus SreA
    • iron regulator.
    • Repressor of 49 genes, in response to iron.
    • GATA-factor (common to many ascomyota). Contains putative iron-sensing domain.
    • Repressed genes incl reductive iron assimilation and siderophore-mediated iron uptake.
    • 23 of 49 organized in clusters.
    • Special cases:
      1. HapX, iron regulator (see above)
      2. mito ornithine carrier (AmcA), supply ornithine.
      3. CgrA, ribosome biosynthesis, thermotolerance, virulence.
      4. Cluster1 - cell-wall degradation? Afu1g03350 1,3-glucanase.
      5. Pep1 - aspartic endopeptidase Afu5g13300, & putative peptidase transporter Afu1g12240. protein degradation. (Pep1 found in sera)
      6. carbon metabolism - glycogen phosphorylase (Afu1g12920), alcohol dehydrogenase (Afu3g01490), isoamyl alcohol oxidase (Afu3g07410) and NAD-dependent formate dehydrogenase (Afu6g04920).
    • motif ATCWGATAA
    • source: [1]
A. fumigatus LaeA
    • regulator of secondary biosynthesis clusters
    • Seems to act independently of SreA
    • Regulates SidE (some biosynthetic function?), but not other cluster genes (sidC, or D).
      • No homolog in A. nidulans
    • Gliotoxin biosynthesis
    • source: [1]
A. fumigatus StuA & BrlA
    • promotors of conidiation (some gene targets overlap)
    • also regulators of secondary biosynthesis (usu related to conidation)
      • StuA 6 biosynthetic clusters
      • BrlA 1 biosynthetic cluster
    • BrlA downregulates rioosomal protein synthesis in response to N limitation (not carbon)
      • seems to be TOR independent
    • source: [2]

References

  1. Schrettl M, Kim HS, Eisendle M, Kragl C, Nierman WC, Heinekamp T, Werner ER, Jacobsen I, Illmer P, Yi H, Brakhage AA, and Haas H. SreA-mediated iron regulation in Aspergillus fumigatus. Mol Microbiol. 2008 Oct;70(1):27-43. DOI:10.1111/j.1365-2958.2008.06376.x | PubMed ID:18721228 | HubMed [1]
  2. Twumasi-Boateng K, Yu Y, Chen D, Gravelat FN, Nierman WC, and Sheppard DC. Transcriptional profiling identifies a role for BrlA in the response to nitrogen depletion and for StuA in the regulation of secondary metabolite clusters in Aspergillus fumigatus. Eukaryot Cell. 2009 Jan;8(1):104-15. DOI:10.1128/EC.00265-08 | PubMed ID:19028996 | HubMed [2]
  3. Krappmann S, Bignell EM, Reichard U, Rogers T, Haynes K, and Braus GH. The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen. Mol Microbiol. 2004 May;52(3):785-99. DOI:10.1111/j.1365-2958.2004.04015.x | PubMed ID:15101984 | HubMed [3]
  4. Chilton IJ, Delaney CE, Barham-Morris J, Fincham DA, Hooley P, and Whitehead MP. The Aspergillus nidulans stress response transcription factor StzA is ascomycete-specific and shows species-specific polymorphisms in the C-terminal region. Mycol Res. 2008 Dec;112(Pt 12):1435-46. DOI:10.1016/j.mycres.2008.06.028 | PubMed ID:18678248 | HubMed [4]
    read this and all below
  5. Zhang L, Wang M, Li R, and Calderone R. Expression of Aspergillus fumigatus virulence-related genes detected in vitro and in vivo with competitive RT-PCR. Mycopathologia. 2005 Oct;160(3):201-6. DOI:10.1007/s11046-005-0141-z | PubMed ID:16205968 | HubMed [5]
  6. Schrettl M, Bignell E, Kragl C, Sabiha Y, Loss O, Eisendle M, Wallner A, Arst HN Jr, Haynes K, and Haas H. Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog. 2007 Sep 28;3(9):1195-207. DOI:10.1371/journal.ppat.0030128 | PubMed ID:17845073 | HubMed [6]
  7. Richie DL, Hartl L, Aimanianda V, Winters MS, Fuller KK, Miley MD, White S, McCarthy JW, Latgé JP, Feldmesser M, Rhodes JC, and Askew DS. A role for the unfolded protein response (UPR) in virulence and antifungal susceptibility in Aspergillus fumigatus. PLoS Pathog. 2009 Jan;5(1):e1000258. DOI:10.1371/journal.ppat.1000258 | PubMed ID:19132084 | HubMed [7]
  8. Gravelat FN, Doedt T, Chiang LY, Liu H, Filler SG, Patterson TF, and Sheppard DC. In vivo analysis of Aspergillus fumigatus developmental gene expression determined by real-time reverse transcription-PCR. Infect Immun. 2008 Aug;76(8):3632-9. DOI:10.1128/IAI.01483-07 | PubMed ID:18490465 | HubMed [8]
All Medline abstracts: PubMed | HubMed