Efficient bioproduction of 5-aminolevulinic acid from renewable bioresources by engineered Saccharomyces cerevisiae

Abstract

5-Aminolevulinic acid (5-ALA), a versatile bio-stimulant, feed additive, and photodynamic agent, was widely used in agriculture and medicine. However, its bioproduction typically relies on refined nitrogen or carbon source and yields remain moderate. Here, we metabolically engineered industrial Saccharomyces cerevisiae AY12a for high-level 5-ALA biosynthesis from renewable low-cost feedstocks. By optimizing key enzymes, enhancing precursor supply, blocking byproducts, alleviating the Crabtree effect, and optimizing fermentation conditions, the engineered strain ALA-27 produced 1,492.8 mg/L 5-ALA in shake flasks and 2,899.7 mg/L in a 5-L bioreactor. Substitution of costly yeast extract and peptone with oilseed meals (namely rapeseed, peanut, and camellia seed meal) resulted in further cost reductions. Using enzymatically hydrolyzed peanut meal, the strain produced 3,289.9 mg/L of 5-ALA—the highest titer reported in yeast to date. This work establishes a sustainable, cost-effective platform for industrial 5-ALA production, and the strategy may be extended to other high-value chemicals.