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B6db references: 29947149

type Journal Article
authors Hertweck C
title Enzymatic Thioamide Formation in Bacterial Antimetabolite Pathway
journal Angew Chem Int Ed Engl
sel selected
ui 29947149
year (2018)
volume 57
number 36
pages 11574-11578
keywords Biosynthesis Enzymology DNA Antimetabolite Natural Product Thioamide
abstract 6-Thioguanine (6TG) is a DNA-targeting therapeutic used in the treatment of various cancers. While 6TG was rationally designed as a proof of concept for antimetabolite therapy, it is also a rare thioamide-bearing bacterial natural product and critical virulence factor of Erwinia amylovorans, plant pathogens causing fire blight. Through gene expression, biochemical assays and mutational analyses we identified a specialized bipartite enzyme system, consisting of an ATP-dependent sulfur transferase (YcfA) and a sulfur-mobilizing enzyme (YcfC), responsible for the peculiar oxygen-by-sulfur substitution. Mechanistic and phylogenetic studies revealed that YcfA-mediated 6TG biosynthesis evolved from ancient tRNA modifications that support translational fidelity. The successful in vitro reconstitution of 6TG thioamidation showed that YcfA employs a specialized sulfur shuttle that markedly differs from universal RNA-related systems. This study sheds light on underexplored enzymatic C-S bond formations in natural product biosynthesis.
last changed 2018/11/27 08:51

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