Journal
ACS CATALYSIS
Volume 13, Issue 22, Pages 15164-15174Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.3c03296
Keywords
benzylisoquinoline alkaloids; norcoclaurinesynthase; crystal structure; catalytic mechanism; enantioselectivity
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Benzylisoquinoline alkaloids (BIAs) are important plant metabolites that offer pharmacological benefits. This study identified non-selective NCS homologues in lotus and revealed the biosynthesis pathway of (R)-BIAs.
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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