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Abstract The direct reduction of CO 2 into one-carbon molecules is key to highly efficient biological CO 2 -fixation. However, this strategy is currently restricted to anaerobic organisms and low redox potentials. In this study, we introduce the CORE cycle, a synthetic metabolic pathway that converts CO 2 to formate at aerobic conditions and ambient CO 2 levels, using only NADPH as a reductant. Combining theoretical pathway design and analysis, enzyme bioprospecting and high-throughput screening, modular assembly and adaptive laboratory evolution, we realize the CORE cycle in vivo and demonstrate that the cycle supports growth of E. coli by supplementing C1-metabolism and serine biosynthesis from CO 2 . We further analyze the theoretical potential of the CORE cycle as a new entry-point for carbon in photorespiration and autotrophy. Overall, our work expands the solution space for biological carbon reduction, offering a promising approach to enhance CO 2 fixation processes such as photosynthesis, and opening avenues for synthetic autotrophy.
Satanowski et al. (Tue,) studied this question.