Abstract Sorbic acid (SA) and its salts are among the world’s most widely used and safest food preservatives, yet their industrial production still relies on fossil fuel-derived feedstocks via chemical synthesis. Here, we report bioproduction of SA through microbial fermentation by decoding its biosynthetic pathway and metabolic engineering of Saccharomyces cerevisiae as a chassis. Here, we identify SA and its amide derivative sorbamide (SN) from Myrothecium sp. FJNU6, representing identification of SA from a microbial source. Genome sequencing and heterologous expression reveal the SA/SN biosynthetic gene cluster, comprising a highly reducing polyketide synthase (SoaA), a hydrolase (SoaB), and an amidotransferase (SoaC). To enable sustainable overproduction, we reconstitute and optimize the SoaA–SoaB pathway in S. cerevisiae through multilevel engineering, including dynamic promoter control, acetyl-CoA/malonyl-CoA pathway enhancement, peroxisomal compartmentalization, and two-stage fed-batch fermentation. These strategies collectively enable a production titer of 1.84 g/L SA in a 50 L bioreactor. This study uncovers a microbial biosynthetic pathway for SA/SN and establishes a microbial platform for SA production, providing a foundation for developing sustainable alternatives to fossil-based manufacturing.
Xiao et al. (Tue,) studied this question.