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

Chakravarti, Arpita; Selvadurai, Kiruthika; Shahoei, Rezvan; Lee, Hugo; Fatma, Shirin; Tajkhorshid, Emad; Huang, Raven H.

doi:10.1074/jbc.ra118.003998

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

Journal Article · Fri Jul 20 00:00:00 EDT 2018 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.ra118.003998· OSTI ID:1569874

Chakravarti, Arpita ^[1]; Selvadurai, Kiruthika ^[1]; Shahoei, Rezvan ^[1]; Lee, Hugo ^[1]; Fatma, Shirin ^[1];

^[1];

^[1]

Univ. of Illinois at Urbana-Champaign, IL (United States)

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 IPP. Collectively, our findings indicate that IPP is an effective substrate of fungal and archaeal viperin enzymes and provide critical insights into the reaction mechanism.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: GM107533; P41GM104601

OSTI ID:: 1569874

Journal Information:: Journal of Biological Chemistry, Vol. 293, Issue 36; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
enzyme
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radical
antiviral agent
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isopentenyl pyrophosphate
radical addition
radical sam enzyme
viperin
interferon-stimulated protein
antiviral cellular factor
antiviral protein
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Title: Reconstitution and substrate specificity for isopentenyl pyrophosphate of the antiviral radical SAM enzyme viperin

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