De novo microbial production of picolinic acid via a short-cut biosynthetic pathway

Abstract

Picolinic acid (PA) is a tryptophan-derived metabolite produced in animals via the kynurenine pathway. Its strong metal-chelating properties and broad antimicrobial, antiviral, and anticancer activities have driven widespread use of PA salts in nutritional supplements and animal feed. Current industrial PA manufacturing depends on petroleum-derived substrates and harsh chemical processes, generating significant environmental burdens. In this work, we develop a sustainable microbial alternative by engineering an artificial shortcut pathway in Escherichia coli. Using chorismate as the entry point, we constructed a hybrid route that couples salicylic acid (SA) biosynthesis with a partial SA degradation module, enabling PA formation in only four enzymatic steps, far fewer than the eleven-step natural pathway. Enhancing SA precursor flux through a pyruvate-mediated metabolic driving force, together with fermentation optimization, allowed the engineered strain to produce 560.02 mg L⁻¹ PA in shake-flask cultures from glucose. This work presents an innovative biocatalytic strategy for PA production and underscores the commercial promise of a biotechnological route capable of replacing conventional chemical synthesis and advancing sustainable PA manufacturing.