Structural and Computational Insights into the Noncanonical Aromatization in Fungal Polyketide Biosynthesis

Aromatic
polyketides, with their diverse structures and biological
activities, have attracted significant scientific interest. Aromatization
reactions are typically performed by aromatases and cyclases associated
with bacterial type II polyketide synthases (PKSs) or product template
and Claisen cyclase domains found in fungal type I nonreducing PKSs.
Intriguingly, our recent study discovered a noncanonical aromatization
mechanism involving a cupin domain-containing enzyme, StrC, in fungal
alkyl salicylaldehyde derivative biosynthesis. Nevertheless, the catalytic
function of StrC largely remained enigmatic. In this study, an in-depth
in vitro characterization of StrC was performed to gain a better understanding
of the reaction mechanism for aromatization. In addition, the X-ray
crystal structure of StrC in the complex with a substrate analogue
was obtained to elucidate the unique active site. Subsequent mutational
experiments identified important amino acid residues for aromatase
activity. Furthermore, a quantum mechanics study provided a plausible
reaction mechanism for aromatization and highlighted the vital role
of StrC in the biosynthetic process. Thus, our study unveils an unknown
paradigm for aromatization in polyketide biosynthesis.