From Rags to Riches: Exploiting the Calvin-Benson-Bassham Cycle for Biomanufacturing

Industrial chemical production largely relies on fossil fuels, resulting in the unavoidable release of carbon dioxide (CO₂) into the atmosphere. The concept of a circular carbon bioeconomy has been proposed to address this issue, wherein CO₂ is captured and used as a raw material for manufacturing new chemicals. Microbial cell factories and, in particular, autotrophic microorganisms capable of utilizing CO₂ as the sole carbon source, emerged as potential catalysts for upcycling CO₂ to valuable products. The Calvin-Benson-Bassham cycle (CBBc), the best-known CO₂ fixation pathway, is widely distributed in Nature. While extensively studied, microbial engineering programmes based on the CBBc remains relatively underexplored. In this review, we discuss avenues towards biotechnological exploitation of the CBBc to engineer CO₂-utilizing microbial cell factories, with a focus on chemically-derived electron donors. We also highlight the advantages and challenges of implementing the CBBc in heterotrophic microbial hosts and its potential to advance a true circular carbon bioeconomy. Moreover, based on the pathway's architecture, we argue about the ideal value-added products to generate from this metabolic route. Altogether, studying and engineering the CBBc in both natural- and synthetic-autotrophs will enhance our understanding on this CO₂ fixation pathway, enabling further exploration of biomanufacturing avenues with CO₂ as feedstock.