C–H Hydroxylation in Paralytic Shellfish Toxin Biosynthesis

The remarkable degree of synthetic selectivity found in Nature is exemplified by the biosynthesis of paralytic shellfish toxins such as saxitoxin. The polycyclic core shared by saxitoxin and its relatives is assembled and subsequently elaborated through the installation of hydroxyl groups with exqui...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2018-09, Vol.140 (37), p.11863-11869
Main Authors: Lukowski, April L, Ellinwood, Duncan C, Hinze, Meagan E, DeLuca, Ryan J, Du Bois, J, Hall, Sherwood, Narayan, Alison R. H
Format: Article
Language:English
Subjects:
Animals
Hydroxylation
Marine Toxins - biosynthesis
Marine Toxins - chemistry
Models, Molecular
Molecular Structure
Shellfish
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Summary:The remarkable degree of synthetic selectivity found in Nature is exemplified by the biosynthesis of paralytic shellfish toxins such as saxitoxin. The polycyclic core shared by saxitoxin and its relatives is assembled and subsequently elaborated through the installation of hydroxyl groups with exquisite precision that is not possible to replicate with traditional synthetic methods. Here, we report the identification of the enzymes that carry out a subset of C–H functionalizations involved in paralytic shellfish toxin biosynthesis. We have shown that three Rieske oxygenases mediate hydroxylation reactions with perfect site- and stereoselectivity. Specifically, the Rieske oxygenase SxtT is responsible for selective hydroxylation of a tricyclic precursor to the famous natural product saxitoxin, and a second Rieske oxygenase, GxtA, selectively hydroxylates saxitoxin to access the oxidation pattern present in gonyautoxin natural products. Unexpectedly, a third Rieske oxygenase, SxtH, does not hydroxylate tricyclic intermediates, but rather a linear substrate prior to tricycle formation, rewriting the biosynthetic route to paralytic shellfish toxins. Characterization of SxtT, SxtH, and GxtA is the first demonstration of enzymes carrying out C–H hydroxylation reactions in paralytic shellfish toxin biosynthesis. Additionally, the reactions of these oxygenases with a suite of saxitoxin-related molecules are reported, highlighting the substrate promiscuity of these catalysts and the potential for their application in the synthesis of natural and unnatural saxitoxin congeners.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.8b08901