On the mechanism of action of the antifungal agent propionate

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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.