On the mechanism of action of the antifungal agent propionate -: Propionyl-CoA inhibits glucose metabolism in Aspergillus nidulans
On the mechanism of action of the antifungal agent propionate -: Propionyl-CoA inhibits glucose metabolism in Aspergillus nidulans
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DOI：
10.1111/j.1432-1033.2004.04255.x
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发表时间：
2004-08-01
期刊：
影响因子：
--
通讯作者：
Buckel, W
中科院分区：
文献类型：
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作者：
Brock, M;Buckel, W
丙酸盐用于保护面包和动物饲料免受霉菌侵害。使用构巢曲霉作为模式生物研究了这种短链脂肪酸的作用模式。丝状真菌能够在丙酸盐上缓慢生长，丙酸盐通过丙酰辅酶A、柠檬酸甲酯和丙酮酸盐氧化为乙酰辅酶A。丙酸盐抑制A. nidulans作用于葡萄糖，但不作用于乙酸盐;后者显示出抑制丙酸盐氧化。当在葡萄糖上生长时，与野生型相比，甲基柠檬酸合酶缺失突变体对培养基中丙酸盐的存在更敏感，并且积累了10倍高水平的丙酰-CoA，其抑制CoA依赖性酶，如丙酮酸脱氢酶、琥珀酰-CoA合成酶和ATP柠檬酸裂解酶。最重要的抑制是丙酮酸脱氢酶，因为它直接影响葡萄糖和丙酸代谢。相反，阻断的琥珀酰辅酶A合成酶可以被琥珀酰辅酶A：乙酸/丙酸辅酶A-转移酶绕过，而ATP柠檬酸裂解酶仅用于生物合成目的。此外，数据相关的抑制真菌聚酮合成丙酰辅酶A的积累，这种辅酶A衍生物。还讨论了丙酰辅酶A在丙酸血症和甲基丙二酸尿症等疾病中对人类的可能毒性。
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.