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Discovery of a Calcium‐Dependent Enzymatic Cascade for the Selective Assembly of Hapalindole‐Type Alkaloids: On the Biosynthetic Origin of Hapalindole U
Author(s) -
Zhu Qin,
Liu Xinyu
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201703932
Subject(s) - biogenesis , enzyme , biosynthesis , chemistry , stereochemistry , calcium , biochemistry , drug discovery , cascade , in vitro , combinatorial chemistry , gene , organic chemistry , chromatography
Hapalindole U ( 4 ) is a validated biosynthetic precursor to ambiguine alkaloids ( Angew. Chem. Int. Ed . 2016 , 55 , 5780), of which biogenetic origin remains unknown. The recent discovery of AmbU4 (or FamC1) protein encoded in the ambiguine biosynthetic pathway ( J. Am. Chem. Soc . 2015 , 137 , 15366), an isomerocyclase that can rearrange and cyclize geranylated indolenine ( 2 ) to a previously unknown 12‐ epi ‐hapalindole U ( 3 ), raised the question whether 3 is a direct precursor to 4 or an artifact arising from the limited in vitro experiments. Here we report a systematic approach that led to the discovery of an unprecedented calcium‐dependent AmbU1‐AmbU4 enzymatic complex for the selective formation of 4 . This discovery refuted the intermediacy of 3 and bridged the missing links in the early‐stage biosynthesis of ambiguines. This work further established the isomerocyclases involved in the biogenesis of hapalindole‐type alkaloids as a new family of calcium‐dependent enzymes, where the metal ions are shown critical for their enzymatic activities and selectivities.