|
type |
Journal Article |
authors |
Hertweck C |
title |
Enzymatic Thioamide Formation in Bacterial Antimetabolite Pathway |
journal |
Angew Chem Int Ed Engl |
Activity |
2.8.1.7 |
Family |
2.8.1.7.c |
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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