Tailoring cyanobacteria as a new platform for highly efficient synthesis of astaxanthin

With the ability to recycle CO2 into value-added chemicals, cyanobacteria have been considered as renewable microbial cell factories. Astaxanthin, a highly valued carotenoid with potent antioxidant activity, could be beneficial to human health. Astaxanthin biosynthesis in engineered chassis has been achieved previously, but it generated a relatively low yield. Here, we successfully constructed a highly efficient astaxanthin biosynthetic pathway in cyanobacterium Synechocystis sp. PCC 6803, and achieved more than a 500-fold increase in astaxanthin production via stepwise reconstruction of the biosynthetic pathway and rational rewiring of the endogenous metabolism. The engineered strain produced up to 29.6 mg/g of astaxanthin (dry cell weight), which is the highest yield reported in the engineered chassis to date. Moreover, multi-omics analyses revealed that establishing a high astaxanthin flux may enhance photosynthesis and central metabolism in the engineered strain to compensate for the depleted pigments, which could be valuable for astaxanthin overproduction. This study presents a novel alternative for high-efficiency biosynthesis of astaxanthin directly from CO2. •Synechocystis sp. PCC 6803 was metabolically engineered to efficiently produce astaxanthin directly from CO2.•The rate-limiting step from β-carotene to astaxanthin was identified and improved.•Overexpression assays were systematically applied to eliminate bottle necks and increase production.•A possible regulatory mechanism involving pigment compensation was elucidated using multi-omics analysis.