title: Blockage of methylcitrate cycle inhibits polyketide production in Aspergillus nidulans.
abstract: Aspergillus nidulans produces the polyketide toxin sterigmatocystin (ST) of which the biosynthetic and pathway specific regulatory genes compose a stc gene cluster. A previous mutagenesis screen identified 23 mutants defective in production of ST. Five mutants constitute a single locus. Genetic complementation and sequencing analysis revealed the mutant locus to be mcsA encoding methylcitrate synthase that converts propionyl-CoA to methylcitrate. Feeding downstream products of methylcitrate synthase, methylcitrate and pyruvate, did not restore ST production in mcsA mutants, indicating that loss of methylcitrate cycle products is not the cause of the ST defect. However, propionate, a precursor for propionyl-CoA, inhibited ST production and induced transcription of mcsA in the wild type. Furthermore, propionate impaired formation of two polyketide spore pigments whereas overexpression of mcsA relieved inhibition of ST production by propionate. Transcription analyses revealed that disruption of mcsA did not affect expression of the specialized fatty acid synthase genes (stcJ and stcK) or polyketide synthase gene (stcA) required for formation of norsolorinic acid (NOR), the first stable intermediate in the ST biosynthetic pathway. Feeding studies showed that NOR but not hexanoic acid (the fatty acid produced by StcJ/StcK and primer unit of StcA) or malonate (source of the extender unit of StcA) restored ST production in the mcsA mutant. We hypothesize that excess buildup of propionyl-CoA in mcsA mutants interferes with polyketide synthase activity.
authors.affiliation: Department of Plant Pathology, University of Wisconsin, 1630 Linden Drive, Madison, WI 53706, USA.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
mesh_terms: D001233:Aspergillus nidulans / Q000201:enzymology* / Q000378:metabolism; D015139:Blotting, Southern; D002208:Caproates / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism*; D002951:Citrates / Q000378:metabolism*; D003470:Culture Media; D004271:DNA, Fungal; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D018942:Macrolides / Q000378:metabolism*; D008314:Malonates / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA; D013241:Sterigmatocystin / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: D002208:Caproates; D002951:Citrates; D003470:Culture Media; D004271:DNA, Fungal; D018942:Macrolides; D008314:Malonates; D009097:Multienzyme Complexes; D011422:Propionates; D012333:RNA, Messenger; D013241:Sterigmatocystin; C037652:hexanoic acid; C030290:malonic acid; D002950:Citrate (si)-Synthase; C092884:methylcitrate synthase