Discovery of a New Family of Dieckmann Cyclases Essential to Tetramic Acid and Pyridone-Based Natural Products Biosynthesis

Bioinformatic analyses indicate that TrdC, SlgL, LipX(2), KirHI, and FacHI belong to a group of highly homologous proteins involved in biosynthesis of actinomycete-derived tirandamycin B, streptolydigin, alpha-lipomycin, kirromycin, and factumycin, respectively. However, assignment of their biosynthetic roles has remained elusive. Gene inactivation and complementation, in vitro biochemical assays with synthetic analogues, point mutations, and phylogenetic tree analyses reveal that these proteins represent a new family of Dieckmann cyclases that drive tetramic acid and pyridone scaffold biosynthesis.