Malonyl-CoA is an important central metabolite serving as the basic building block for the microbial synthesis of many pharmaceutically interesting polyketides, but also fatty acid-derived compounds including biofuels. Especially Saccharomyces cerevisiae, Escherichia coli, and Corynebacterium glutamicum have been engineered towards microbial synthesis of such compounds in recent years. However, developed strains and processes often suffer from insufficient productivity. Usually, tightly regulated intracellular malonyl-CoA availability is regarded as the decisive bottleneck limiting overall product formation. Therefore, metabolic engineering towards improved malonyl-CoA availability is essential to design efficient microbial cell factories for the production of polyketides and fatty acid derivatives. This review article summarizes metabolic engineering strategies to improve intracellular malonyl-CoA formation in industrially relevant microorganisms and its impact on productivity and product range, with a focus on polyketides and other malonyl-CoA-dependent products.Key Points• Malonyl-CoA is the central building block of polyketide synthesis.• Increasing acetyl-CoA supply is pivotal to improve malonyl-CoA availability.• Improved acetyl-CoA carboxylase activity increases availability of malonyl-CoA.• Fatty acid synthesis as an ambivalent target to improve malonyl-CoA supply.

中文翻译：

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工程化微生物宿主中细胞内丙二酰辅酶A的可用性及其对聚酮化合物和脂肪酸合成的影响。

丙二酰辅酶A是重要的中心代谢产物，是微生物合成许多可药用的聚酮化合物以及包括生物燃料在内的脂肪酸衍生化合物的基本组成部分。近年来，特别是酿酒酵母，大肠杆菌和谷氨酸棒状杆菌已被工程化以用于此类化合物的微生物合成。然而，发达的菌株和工艺通常遭受生产率不足的困扰。通常，严格调节的细胞内丙二酰辅酶A的可用性被认为是限制整体产品形成的决定性瓶颈。因此，为改善丙二酰辅酶A的利用率而进行的代谢工程对于设计高效的微生物细胞工厂以生产聚酮化合物和脂肪酸衍生物至关重要。