title: On the mechanism of action of the antifungal agent propionate.
abstract: Propionate is used to protect bread and animal feed from moulds. The mode of action of this short-chain fatty acid was studied using Aspergillus nidulans as a model organism. The filamentous fungus is able to grow slowly on propionate, which is oxidized to acetyl-CoA via propionyl-CoA, methylcitrate and pyruvate. Propionate inhibits growth of A. nidulans on glucose but not on acetate; the latter was shown to inhibit propionate oxidation. When grown on glucose a methylcitrate synthase deletion mutant is much more sensitive towards the presence of propionate in the medium as compared to the wild-type and accumulates 10-fold higher levels of propionyl-CoA, which inhibits CoA-dependent enzymes such as pyruvate dehydrogenase, succinyl-CoA synthetase and ATP citrate lyase. The most important inhibition is that of pyruvate dehydrogenase, as this affects glucose and propionate metabolism directly. In contrast, the blocked succinyl-CoA synthetase can be circumvented by a succinyl-CoA:acetate/propionate CoA-transferase, whereas ATP citrate lyase is required only for biosynthetic purposes. In addition, data are presented that correlate inhibition of fungal polyketide synthesis by propionyl-CoA with the accumulation of this CoA-derivative. A possible toxicity of propionyl-CoA for humans in diseases such as propionic acidaemia and methylmalonic aciduria is also discussed.
authors.affiliation: Laboratorium für Mikrobiologie, Universität Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brock
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Buckel
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism; D000106:Acetate-CoA Ligase / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001233:Aspergillus nidulans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D015256:Coenzyme A-Transferases / Q000378:metabolism; D003116:Color; D003470:Culture Media / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway; D011422:Propionates / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism; D013170:Spores / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D000935:Antifungal Agents; D003470:Culture Media; D011422:Propionates; C009061:propionyl-coenzyme A; D000105:Acetyl Coenzyme A; D002244:Carbon; D019289:Pyruvic Acid; D001275:ATP Citrate (pro-S)-Lyase; D015256:Coenzyme A-Transferases; D000106:Acetate-CoA Ligase; D005947:Glucose