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Publication Abstract from PubMed

Chalcone is a privileged natural product skeleton for drug discovery, and retrochalcone represents a group of nonclassical chalcones with a distinctive oxygen substitution pattern. Echinatin, a hepatoprotective agent, is a retrochalcone derived from Glycyrrhiza inflata. Despite their initial discovery half a century ago, the biosynthetic mechanisms of retrochalcones have remained elusive. In this work, we identified a ketoreductase, GinKR1, which selectively catalyzes the reduction of the 1-carbonyl group of the dibenzoylmethane precursor 2'-O-methyllicodione, followed by spontaneous dehydration to form the retrochalcone skeleton. Our findings reveal that the A and B rings of retrochalcones are derived from the shikimate and polyketide pathways, respectively, which are reversed to normal chalcones. In addition, (18)O isotope labeling verifies that the carbonyl oxygen of retrochalcones is derived from the hydroxyl group introduced by a flavanone 2-hydroxylase. The complete biosynthetic pathway of echinatin was elucidated by identifying six enzymes from G. inflata. Moreover, we determined the crystal structure of GinKR1 and identified a critical alpha10 helix responsible for its regioselectivity. With this alpha10 helix as a marker, we further discovered homologous genes of GinKR1 from 185 plant species. This study elucidates the biosynthetic pathway and underlying mechanisms of retrochalcones.

Elucidating the Biosynthetic Pathway and Mechanisms of Retrochalcones.,Ye L, Wang ZL, Xu ZQ, Tian YG, Zhang M, Abe I, Ye M J Am Chem Soc. 2025 Aug 13;147(32):29205-29214. doi: 10.1021/jacs.5c08070. Epub , 2025 Jul 29. PMID:40729162^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.