Reconstitution and substrate specificity for isopentenyl pyrophosphate of the antiviral radical SAM enzyme viperin

The Journal of Biological Chemistry
Arpita ChakravartiRaven H Huang

Abstract

Viperin is a radical SAM enzyme that has been shown to possess antiviral activity against a broad spectrum of viruses; however, its molecular mechanism is unknown. We report here that recombinant fungal and archaeal viperin enzymes catalyze the addition of the 5'-deoxyadenosyl radical (5'-dA•) to the double bond of isopentenyl pyrophosphate (IPP), producing a new compound we named adenylated isopentyl pyrophosphate (AIPP). The reaction is specific for IPP, as other pyrophosphate compounds involved in the mevalonate biosynthetic pathway did not react with 5'-dA• Enzymatic reactions employing IPP derivatives as substrates revealed that any chemical change in IPP diminishes its ability to be an effective substrate of fungal viperin. Mutational studies disclosed that the hydroxyl group on the side chain of Tyr-245 in fungal viperin is the likely source of hydrogen in the last step of the radical addition, providing mechanistic insight into the radical reaction catalyzed by fungal viperin. Structure-based molecular dynamics (MD) simulations of viperin interacting with IPP revealed a good fit of the isopentenyl motif of IPP to the active site cavity of viperin, unraveling the molecular basis of substrate specificity of viperin for IP...Continue Reading

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Citations

Jan 26, 2020·The Journal of Biological Chemistry·Arti B DumbrepatilE Neil G Marsh
Jun 18, 2020·The Journal of Biological Chemistry·Soumi Ghosh, E Neil G Marsh
Jul 1, 2020·Annual Review of Virology·Efraín E Rivera-SerranoCraig E Cameron
Mar 30, 2021·Journal of the American Chemical Society·Ayesha M Patel, E Neil G Marsh
May 6, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tamra C Blue, Katherine M Davis
Jan 10, 2020·Biochemistry·Michael K FenwickSteven E Ealick

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