A Path toward SARS-CoV-2 Attenuation: Metabolic Pressure on CTP Synthesis Rules the Virus Evolution.

Autor:	Ou Z; BGI-Shenzhen, Shenzhen, China.; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China., Ouzounis C; Biological Computation and Process Laboratory, Centre for Research and Technology Hellas, Chemical Process and Energy Resources Institute, Thessalonica, Greece., Wang D; BGI-Shenzhen, Shenzhen, China.; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China., Sun W; BGI-Shenzhen, Shenzhen, China.; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China.; BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China., Li J; BGI-Shenzhen, Shenzhen, China.; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China., Chen W; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China.; BGI PathoGenesis Pharmaceutical Technology, BGI-Shenzhen, Shenzhen, China., Marlière P; TESSSI, The European Syndicate of Synthetic Scientists and Industrialists, Paris, France., Danchin A; Kodikos Labs, Institut Cochin, Paris, France.; School of Biomedical Sciences, Li KaShing Faculty of Medicine, Hong Kong University, Pokfulam, Hong Kong.
Jazyk:	angličtina
Zdroj:	Genome biology and evolution [Genome Biol Evol] 2020 Dec 06; Vol. 12 (12), pp. 2467-2485.
DOI:	10.1093/gbe/evaa229
Abstrakt:	In the context of the COVID-19 pandemic, we describe here the singular metabolic background that constrains enveloped RNA viruses to evolve toward likely attenuation in the long term, possibly after a step of increased pathogenicity. Cytidine triphosphate (CTP) is at the crossroad of the processes allowing SARS-CoV-2 to multiply, because CTP is in demand for four essential metabolic steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope, it is a critical building block of the host transfer RNAs synthesis and it is required for synthesis of dolichol-phosphate, a precursor of viral protein glycosylation. The CCA 3'-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. This unique metabolic setup allowed us to highlight and provide a raison d'être to viperin, an enzyme of innate antiviral immunity, which synthesizes 3'-deoxy-3',4'-didehydro-CTP as an extremely efficient antiviral nucleotide. (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu