Metabolic Engineering of Microbial Cell Factories for Sustainable Production of Glycolic Acid: Pathways, Chassis, and Strategies toward Poly(glycolic acid) Bioplastics

The environmental challenges associated with fossil fuel-derived plastics have intensified the demand for sustainable and biodegradable alternatives. Poly(glycolic acid) (PGA) is a promising substitute for conventional plastics, but its industrial production is limited by the cost and availability of its monomer, glycolic acid (GA). Traditional GA synthesis relies on petrochemical processes involving hazardous reagents and high energy input, necessitating greener alternatives. Microbial biosynthesis of GA presents a more sustainable production route. This review systematically summarizes recent advances in GA bioproduction, covering key biosynthetic pathways (glyoxylate shunt pathway, C5-sugar cleavage pathways, and emerging novel routes), diverse microbial chassis, and substrate utilization strategies. Their metabolic characteristics, theoretical carbon conversion efficiencies, advantages, and limitations are comparatively discussed. We further highlight metabolic engineering and synthetic biology approaches, including enzyme optimization, elimination of competing pathways, cofactor balancing, flux redistribution, and dynamic regulation using biosensors. In addition, critical aspects for industrialization are discussed, including downstream processing technologies, stress tolerance engineering, techno-economic analysis (TEA), and life cycle assessment (LCA). Emerging strategies such as membrane-based separations and in situ product removal (ISPR) are emphasized for improving process efficiency. Overall, integrating systems metabolic engineering with AI-assisted design and process optimization is expected to enable scalable, cost-effective, and low-carbon GA production, supporting the development of PGA-based bioplastics and a circular bioeconomy.