Gonzalez-Garcia R Axayacatl, Nielsen Lars K, Marcellin Esteban
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD 4072, Australia.
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, DK-2800 Kgs Lyngby, Denmark.
Metabolites. 2020 Jun 1;10(6):228. doi: 10.3390/metabo10060228.
Polyketides are a remarkable class of natural products with diverse functional and structural diversity. The class includes many medicinally important molecules with antiviral, antimicrobial, antifungal and anticancer properties. Native bacterial, fungal and plant hosts are often difficult to cultivate and coax into producing the desired product. As a result, has been used for the heterologous production of polyketides, with the production of 6-deoxyerythronolide B (6-dEB) being the first example. Current strategies for production in require feeding of exogenous propionate as a source for the precursors propionyl-CoA and -methylmalonyl-CoA. Here, we show that heterologous polyketide production is possible from glucose as the sole carbon source. The heterologous expression of eight genes from the Wood-Werkman cycle found in Propionibacteria, in combination with expression of the 6-dEB synthases DEBS1, DEBS2 and DEBS3 resulted in 6-dEB formation from glucose as the sole carbon source. Our results show that the Wood-Werkman cycle provides the required propionyl-CoA and the extender unit -methylmalonyl-CoA to produce up to 0.81 mg/L of 6-dEB in a chemically defined media.
聚酮化合物是一类具有多样功能和结构多样性的天然产物。该类别包括许多具有抗病毒、抗菌、抗真菌和抗癌特性的重要药用分子。天然的细菌、真菌和植物宿主通常难以培养并诱导其产生所需产物。因此，已被用于聚酮化合物的异源生产，其中6-脱氧红霉内酯B（6-dEB）的生产是首个例子。目前在[具体宿主]中进行生产的策略需要添加外源丙酸作为前体丙酰辅酶A和甲基丙二酰辅酶A的来源。在此，我们表明以葡萄糖作为唯一碳源进行异源聚酮化合物生产是可行的。在丙酸杆菌中发现的伍德-韦克曼循环的八个基因的异源表达，与6-dEB合酶DEBS1、DEBS2和DEBS3的表达相结合，使得以葡萄糖作为唯一碳源时能够形成6-dEB。我们的结果表明，伍德-韦克曼循环提供了所需的丙酰辅酶A和延伸单元甲基丙二酰辅酶A，从而在化学限定培养基中能够产生高达0.81毫克/升的6-dEB。
