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 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.