Rewiring carbon metabolism in yeast for high level production of aromatic chemicals

TLDR

Microbial production of bioactive plant compounds is a safe, cost‑competitive, scalable approach, yet aromatic amino‑acid derived chemicals remain a metabolic engineering challenge. The study constructs a Saccharomyces cerevisiae platform strain to produce high levels of p‑coumaric acid, an AAA‑derived precursor for many valuable chemicals. This is achieved by engineering the AAA biosynthesis pathway, adding a phosphoketalose route to redirect glycolytic flux to erythrose‑4‑phosphate, and tuning carbon distribution via promoter replacement of key genes between glycolysis and AAA synthesis. The engineered strain reaches a maximum p‑coumaric acid titer of 12.5 g L⁻¹ and a yield of 154.9 mg g⁻¹ glucose.

Abstract

The production of bioactive plant compounds using microbial hosts is considered a safe, cost-competitive and scalable approach to their production. However, microbial production of some compounds like aromatic amino acid (AAA)-derived chemicals, remains an outstanding metabolic engineering challenge. Here we present the construction of a Saccharomyces cerevisiae platform strain able to produce high levels of p-coumaric acid, an AAA-derived precursor for many commercially valuable chemicals. This is achieved through engineering the AAA biosynthesis pathway, introducing a phosphoketalose-based pathway to divert glycolytic flux towards erythrose 4-phosphate formation, and optimizing carbon distribution between glycolysis and the AAA biosynthesis pathway by replacing the promoters of several important genes at key nodes between these two pathways. This results in a maximum p-coumaric acid titer of 12.5 g L−1 and a maximum yield on glucose of 154.9 mg g−1.