Connection of propionyl-CoA metabolism to polyketide biosynthesis in Aspergillus nidulans.
Propionyl-CoA is an intermediate metabolite produced through a variety of pathways including thioesterification of propionate and catabolism of odd chain fatty acids and select amino acids. Previously, we found that disruption of the methylcitrate synthase gene, mcsA, which blocks propionyl-CoA utilization, as well as growth on propionate impaired production of several polyketides-molecules typically derived from acetyl-CoA and malonyl-CoA-including sterigmatocystin (ST), a potent carcinogen, and the conidiospore pigment. Here we describe three lines of evidence that demonstrate that excessive propionyl-CoA levels in the cell can inhibit polyketide synthesis. First, inactivation of a putative propionyl-CoA synthase, PcsA, which converts propionate to propionyl-CoA, restored polyketide production and reduced cellular propionyl-CoA content in a DeltamcsA background. Second, inactivation of the acetyl-CoA synthase, FacA, which is also involved in propionate utilization, restored polyketide production in the DeltamcsA background. Third, fungal growth on several compounds (e.g., heptadecanoic acid, isoleucine, and methionine) whose catabolism includes the formation of propionyl-CoA, were found to inhibit ST and conidiospore pigment production. These results demonstrate that excessive propionyl-CoA levels in the cell can inhibit polyketide synthesis.
Zhang
Yong-Qiang
YQ
Department of Plant Pathology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Brock
Matthias
M
Keller
Nancy P
NP
D000106:Acetate-CoA Ligase / Q000037:antagonists & inhibitors; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism*; D000595:Amino Acid Sequence; D001233:Aspergillus nidulans / Q000201:enzymology*; D002950:Citrate (si)-Synthase / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D008314:Malonates / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D043586:Methylmalonyl-CoA Decarboxylase / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D011422:Propionates / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013241:Sterigmatocystin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000214:Acyl Coenzyme A; D008314:Malonates; D011422:Propionates; D013241:Sterigmatocystin; C009061:propionyl-coenzyme A; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D002950:Citrate (si)-Synthase; C092884:methylcitrate synthase; D000106:Acetate-CoA Ligase; D043586:Methylmalonyl-CoA Decarboxylase