Microbial production of medium-chain-length diols: Current stage and perspectives

Medium-chain-length α,ω-diols (mcl-diols) are valuable and versatile molecules with applications in polymers, lubricants, and specialty chemicals. Currently, their production relies on fossil-based industrial processes, but there is a growing effort to develop sustainable alternatives. Microbial biosynthesis has emerged as a promising approach, with successful mcl-diols production from various renewable substrates, including n-alkanes, fatty acids, cycloalkanes, adipic acid, and glucose. This review summarizes and compares different microbial mcl-diols biosynthetic pathways, highlighting their strengths and limitations. A generalized pathway applicable to various chain lengths is proposed, based on fatty acid biosynthesis or the reversed β-oxidation pathway. Critical challenges remain, such as accelerating microbial chassis selection and optimization, enhancing the activity of rate-limiting enzymes, and mitigating the toxicity of intermediates and end products. To accelerate the commercialization of microbial mcl-diols production, future efforts should focus on metabolic engineering strategies, advanced protein engineering techniques, and process optimization. Additionally, the integration of synthetic biology, adaptive laboratory evolution, and AI-driven enzyme design can further enhance pathway efficiency and reduce production costs. This review provides insights into the current progress and future directions for sustainable mcl-diols biosynthesis, contributing to the broader goal of replacing fossil-based chemicals with bio-based alternatives.