Download MendeleyStructural Insight into the Substrate Scope of Viperin and Viperin-like Enzymes from Three Domains of Life.
Lachowicz, J.C., Gizzi, A.S., Almo, S.C., Grove, T.L.(2021) Biochemistry 60: 2116-2129
- PubMed: 34156827
- DOI: https://doi.org/10.1021/acs.biochem.0c00958
- Primary Citation of Related Structures:
7N7H, 7N7I - PubMed Abstract:
Viperin is a member of the radical S -adenosylmethionine superfamily and has been shown to restrict the replication of a wide range of RNA and DNA viruses. We recently demonstrated that human viperin (HsVip) catalyzes the conversion of CTP to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP or ddh-synthase), which acts as a chain terminator for virally encoded RNA-dependent RNA polymerases from several flaviviruses. Viperin homologues also exist in non-chordate eukaryotes (e.g., Cnidaria and Mollusca), numerous fungi, and members of the archaeal and eubacterial domains. Recently, it was reported that non-chordate and non-eukaryotic viperin-like homologues are also ddh-synthases and generate a diverse range of ddhNTPs, including the newly discovered ddhUTP and ddhGTP. Herein, we expand on the catalytic mechanism of mammalian, fungal, bacterial, and archaeal viperin-like enzymes with a combination of X-ray crystallography and enzymology. We demonstrate that, like mammalian viperins, these recently discovered viperin-like enzymes operate through the same mechanism and can be classified as ddh-synthases. Furthermore, we define the unique chemical and physical determinants supporting ddh-synthase activity and nucleotide selectivity, including the crystallographic characterization of a fungal viperin-like enzyme that utilizes UTP as a substrate and a cnidaria viperin-like enzyme that utilizes CTP as a substrate. Together, these results support the evolutionary conservation of the ddh-synthase activity and its broad phylogenetic role in innate antiviral immunity.
Organizational Affiliation:
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
