Cowan et al. 2025 Source Data.xlsx

Microbial bioproduction using one-carbon (C1) feedstocks has the potential to decarbonize the manufacturing of materials, fuels, and chemicals. Formate is a promising C1 feedstock, and the realization of industrial, formatotrophic platform organisms is a key goal for C1-based bioproduction. So far, a major limitation for synthetic formatotrophy has been slow energy supply due to slow formate dehydrogenase activity. Here, we implement a fast, metal-dependent formate dehydrogenase complex in a synthetic formatotrophic <i>Escherichia coli</i> utilizing the reductive glycine pathway. After a short-term evolution, we demonstrate formatotrophic growth of<i> E. coli </i>with a doubling time of less than 4.5 hours, comparable to the fastest natural formatotrophs. To further explore the potential of a formate-based bioeconomy, this strain is engineered to produce mevalonate, as well as the terpenoid and aviation fuel precursor isoprenol, using formate we generate directly from the electrochemical reduction of CO₂. The highest reported titer of any bioproduct from formate is achieved, with the production of 3.8 g/L of mevalonate. Additionally, the abundant and recalcitrant polymer lignin is chemically decomposed into a formate-rich mixture of small organic acids and subsequently bioconverted into mevalonate. Overall, the described fast-growing, industrial, formatotrophic strain demonstrates that a sustainable formate bioeconomy is within reach.

以一碳（C1）原料开展微生物生物制造，有望实现材料、燃料与化学品制造的脱碳。甲酸盐是极具应用前景的C1原料，构建工业化的甲酸营养型（formatotrophic）平台微生物，是基于C1的生物制造的核心目标之一。迄今为止，合成甲酸营养型代谢的主要限制因素为甲酸脱氢酶活性偏低引发的能量供应不足。本研究在搭载还原甘氨酸途径的合成甲酸营养型大肠杆菌<i>Escherichia coli</i>中，引入了一种快速的金属依赖性甲酸脱氢酶复合物。经过短期适应性进化后，我们实现了大肠杆菌的甲酸营养型生长，其倍增时间不足4.5小时，可与目前已知的最快天然甲酸营养型微生物相媲美。为进一步探索基于甲酸盐的生物经济潜力，我们对该菌株进行工程化改造，使其能够利用直接从CO₂电化学还原制备的甲酸盐，生产甲羟戊酸以及萜类化合物与航空燃料前体异戊烯醇。本研究实现了目前已报道的最高滴度的甲酸盐基生物产品，甲羟戊酸产量可达3.8 g/L。此外，我们将丰富且难降解的木质素聚合物化学降解为富含甲酸盐的小分子有机酸混合物，随后将其生物转化为甲羟戊酸。综上，本研究构建的快速生长、工业化的甲酸营养型菌株，证明了可持续的甲酸盐生物经济具有现实可行性。