Discovery, Structure, and Mechanism of the (R, S)-Norcoclaurine Synthase for the Chiral Synthesis of Benzylisoquinoline Alkaloids
ACS Catalysis(2023)
Abstract
Benzylisoquinoline alkaloids (BIAs) are key plant metabolites that offer significant pharmacological benefits. While most naturally isolated BIAs are identified as (S)-enantiomers, (R)-configured BIAs are also abundant in specific species. However, the formation mechanism of (R)-enantiospecific BIAs remains largely unknown. Norcoclaurine synthase (NCS)-catalyzed Pictet-Spengler condensation is responsible for the BIAs scaffold formation and establishing a unique chiral carbon center. Nevertheless, all NCSs hitherto identified were strictly (S)-selective. Herein, five NCS homologues in lotus were identified and functionally characterized to be without enantiopreference, namely, being capable of producing (R)-norcoclaurine. We revealed the crystal structure of NnNCS1, one of the five identified NnNCS homologues, showing the enzyme's typical pathogenesis-related protein 10-fold and an active dimeric form. Guided by the mechanistic information from quantum chemical calculations, the single-point mutation of Ile43, Leu60, and Phe101 leads to (R)-enantiospecific mutants. This study unravels the previously obscure pathway of (R)-BIA biosynthesis, thereby providing valuable enzymatic tools for the synthetic biology of (R)-configured BIAs.
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Key words
benzylisoquinoline alkaloids,norcoclaurinesynthase,crystal structure,catalytic mechanism,enantioselectivity
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