Biosynthesis Based on One-Carbon Mixotrophy

Recent advances in biosynthesis using one-carbon (C1) compounds (e.g., CO2 and syngas) have led to first process examples of industrial demonstration for producing C1-based chemicals. In these processes, several bottlenecks such as mass-transfer limitations of substrates, limited supply of energy (ATP), and reducing equivalents and thus low cell growth and product formation rate are observed that severely hinder their technical application. As an alternative approach, C1-mixotrophy is proposed which involves co-utilization of C1 and organic substrates as complementing heterotrophic and autotrophic biosynthesis. Bulk and fine chemicals are reported to be efficiently synthetized in such a way. In this chapter, examples of C1-mixotrophy are presented and discussed to demonstrate their potential and perks. In acetogenic mixotrophy, the reductive acetyl-CoA pathway is harnessed as C1 fixation module by using native acetogens as cellular machineries. The highly adapted and efficient carbon fixation is enhanced by co-supply of reducing equivalents and energy from organic substrate. Alternatively, methanol as a highly reduced C1 compound provides carbon building blocks and reducing equivalents in methylotrophic mixotrophy, which is feasible for native and synthetic methylotrophs, broadening the range of applicable hosts. Another possibility is to make use of the anaplerotic reactions of C1 fixation naturally existing in heterotrophs. Re-wiring of carbon metabolism can lead to forced C1 fixation into the final products, thereby overcoming the inherent limitation of achievable product yield of heterotrophs. In a short to middle term, using native or synthetic pathways of C1 fixation module in a mixotrophy represents a promising and practicable bioprocess strategy. To this end, more quantitative and systematic studies regarding intracellular interactions of C1-fixation and catabolic modules are needed. Possible catabolite repression or other interfering native regulatory mechanisms in mixotrophy should be better studied. Stepwise engineering of established production strains is a necessary effort to raise the industrial relevance of C1-based biosynthesis.