Structural basis for sensitivity and acquired resistance of fungal cap guanine-N7 methyltransferases to the antifungal antibiotic sinefungin
Daniel J Nilson, Beate Schwer, Steven C Almo, Stewart Shuman, Agnidipta Ghosh
TL;DR
This study explains how the antibiotic sinefungin inhibits fungal mRNA capping enzymes and how resistance can develop.
Contribution
The study reveals the structural basis for sinefungin's antifungal activity and resistance through crystal structures and genetic analysis.
Findings
Sinefungin inhibits fungal cap methyltransferases with much higher potency than SAH.
Crystal structures show how sinefungin forms hydrogen bonds with GTP for higher affinity.
A conserved tyrosine residue is critical for sinefungin potency and resistance.
Abstract
The essential enzyme messenger RNA (mRNA) (guanine-N7) methyltransferase catalyzes S-adenosylmethionine (SAM)-dependent conversion of GpppRNA ends to the m7GpppRNA cap structure characteristic of eukaryal mRNAs. The antibiotic sinefungin (SFG) is a SAM analog in which the S-CH3 sulfonium moiety of SAM is replaced by a C-NH2 amine. Available evidence indicates that the antifungal activity of SFG is exerted via inhibition of fungal cap methyltransferase Abd1. Here we report that recombinant Kluyveromyces lactis and Saccharomyces cerevisiae Abd1 are 240-fold and 485-fold more sensitive to inhibition by SFG than by the reaction product S-adenosylhomocysteine (SAH). Crystal structures of K. lactis and S. cerevisiae Abd1 as binary complexes with SAH or SFG and ternary complexes with GTP•SFG highlight how SFG makes two hydrogen bonds from its C-NH2 amine to the guanine-O6 and -N7 atoms of GTP…
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Taxonomy
TopicsAntifungal resistance and susceptibility · Entomopathogenic Microorganisms in Pest Control · Plant Pathogens and Fungal Diseases