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Synthesis

Indole alkaloid biosynthetic pathways unraveled

Enzymatic cascade reactions make three natural products with promising antimicrobial and antitumor activity from one precursor

by Stu Borman
March 13, 2017 | APPEARED IN VOLUME 95, ISSUE 11

Indole-based alkaloid natural products such as fischerindoles and hapalindoles have promising antimicrobial and antitumor activities, but they are difficult to make synthetically. New findings on how cyanobacteria biosynthesize them could help guide future synthetic efforts. Xinyu Liu and Qin Zhu at the University of Pittsburgh have discovered that U-protein enzymes catalyze cascade reactions that structurally diversify a common precursor into different indole alkaloids (Chem. Commun. 2017, DOI: 10.1039/c7cc00782e). For example, three of the enzymes—WelU1, WelU3, and AmbU4—convert a single indolenine into a tetracyclic fischerindole, a tricyclic hapalindole, and a tetracyclic hapalindole, respectively. Each enzyme’s cascade reaction includes a Cope rearrangement, an aza-Prins cyclization, and a carbocation-deposition step. The indolenine precursor and its derivatives are structural isomers, so the cascades in effect are multistep rearrangements. With U-protein enzymes now in hand—they can be isolated from cyanobacteria—Liu believes it will be easier to synthesize diverse members of this family of bioactive natural products in the laboratory.

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The enzymes AmbU4, WelU1, and WelU3 use cascade reactions to convert a common indolenine precursor into three natural products.
The enzymes AmbU4, WelU1, and WelU3 use cascade reactions to convert a common indolenine precursor into three natural products.
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