Biosynthesis of the l -Pyridylalanine Moiety in Antimycobacterial Pyridomycin via a PKS-NRPS Hybrid System

This study elucidates the de novo biosynthesis of 3-(3-pyridyl)-l-alanine (3-Pal), a key structural motif of the antimycobacterial cyclodepsipeptide pyridomycin, through a coordinated nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS) hybrid system. Nicotinic acid and 1,3-bisphosphoglycerate (1,3-BPG) are separately activated and loaded onto carrier proteins, forming two tethered intermediates. The type I PKS enzyme Pyr9 catalyzes their condensation, followed by hydrolysis and transamination, ultimately yielding 3-Pal. This work significantly expands the functional versatility of NRPS-PKS biosynthetic machinery.