Zhang Yong-Qiang, Brock Matthias, Keller Nancy P
Department of Plant Pathology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Genetics. 2004 Oct;168(2):785-94. doi: 10.1534/genetics.104.027540.
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.
丙酰辅酶A是一种中间代谢产物，可通过多种途径产生，包括丙酸的硫酯化、奇数链脂肪酸的分解代谢以及特定氨基酸的分解代谢。此前，我们发现破坏甲基柠檬酸合酶基因mcsA（该基因会阻断丙酰辅酶A的利用）以及在丙酸上的生长会损害几种聚酮化合物的产生，这些聚酮化合物分子通常源自乙酰辅酶A和丙二酰辅酶A，包括强效致癌物柄曲霉素（ST）和分生孢子色素。在此，我们描述了三条证据，证明细胞内丙酰辅酶A水平过高会抑制聚酮化合物的合成。首先，在ΔmcsA背景下，将丙酸转化为丙酰辅酶A的假定丙酰辅酶A合成酶PcsA失活，可恢复聚酮化合物的产生并降低细胞内丙酰辅酶A的含量。其次，同样参与丙酸利用的乙酰辅酶A合成酶FacA失活，在ΔmcsA背景下恢复了聚酮化合物的产生。第三，发现真菌在几种分解代谢包括丙酰辅酶A形成的化合物（如十七烷酸、异亮氨酸和蛋氨酸）上生长会抑制ST和分生孢子色素的产生。这些结果表明，细胞内丙酰辅酶A水平过高会抑制聚酮化合物的合成。
