Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.

The RNA guanylyltransferase (GTase) is involved in the synthesis of the (m7)Gppp-RNA cap structure found at the 5' end of eukaryotic mRNAs. GTases are members of the covalent nucleotidyl transferase superfamily, which also includes DNA and RNA ligases. GTases catalyze a two-step reaction in whi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maude Tremblay-Létourneau, Simon Despins, Isabelle Bougie, Martin Bisaillon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7835f4b3119543c9be163e02345e506a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7835f4b3119543c9be163e02345e506a
record_format	dspace
spelling	oai:doaj.org-article:7835f4b3119543c9be163e02345e506a2021-11-04T06:08:29ZVirtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.1932-620310.1371/journal.pone.0024806https://doaj.org/article/7835f4b3119543c9be163e02345e506a2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21935470/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The RNA guanylyltransferase (GTase) is involved in the synthesis of the (m7)Gppp-RNA cap structure found at the 5' end of eukaryotic mRNAs. GTases are members of the covalent nucleotidyl transferase superfamily, which also includes DNA and RNA ligases. GTases catalyze a two-step reaction in which they initially utilize GTP as a substrate to form a covalent enzyme-GMP intermediate. The GMP moiety is then transferred to the diphosphate end of the RNA transcript in the second step of the reaction to form the Gppp-RNA structure. In the current study, we used a combination of virtual database screening, homology modeling, and biochemical assays to search for novel GTase inhibitors. Using this approach, we demonstrate that mycophenolic acid (MPA) can inhibit the GTase reaction by preventing the catalytic transfer of the GMP moiety onto an acceptor RNA. As such, MPA represents a novel type of inhibitor against RNA guanylyltransferases that inhibits the second step of the catalytic reaction. Moreover, we show that the addition of MPA to S. cerevisiae cells leads to a reduction of capped mRNAs. Finally, biochemical assays also demonstrate that MPA can inhibit DNA ligases through inhibition of the second step of the reaction. The biological implications of these findings for the MPA-mediated inhibition of members of the covalent nucleotidyl superfamily are discussed.Maude Tremblay-LétourneauSimon DespinsIsabelle BougieMartin BisaillonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24806 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maude Tremblay-Létourneau Simon Despins Isabelle Bougie Martin Bisaillon Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
description	The RNA guanylyltransferase (GTase) is involved in the synthesis of the (m7)Gppp-RNA cap structure found at the 5' end of eukaryotic mRNAs. GTases are members of the covalent nucleotidyl transferase superfamily, which also includes DNA and RNA ligases. GTases catalyze a two-step reaction in which they initially utilize GTP as a substrate to form a covalent enzyme-GMP intermediate. The GMP moiety is then transferred to the diphosphate end of the RNA transcript in the second step of the reaction to form the Gppp-RNA structure. In the current study, we used a combination of virtual database screening, homology modeling, and biochemical assays to search for novel GTase inhibitors. Using this approach, we demonstrate that mycophenolic acid (MPA) can inhibit the GTase reaction by preventing the catalytic transfer of the GMP moiety onto an acceptor RNA. As such, MPA represents a novel type of inhibitor against RNA guanylyltransferases that inhibits the second step of the catalytic reaction. Moreover, we show that the addition of MPA to S. cerevisiae cells leads to a reduction of capped mRNAs. Finally, biochemical assays also demonstrate that MPA can inhibit DNA ligases through inhibition of the second step of the reaction. The biological implications of these findings for the MPA-mediated inhibition of members of the covalent nucleotidyl superfamily are discussed.
format	article
author	Maude Tremblay-Létourneau Simon Despins Isabelle Bougie Martin Bisaillon
author_facet	Maude Tremblay-Létourneau Simon Despins Isabelle Bougie Martin Bisaillon
author_sort	Maude Tremblay-Létourneau
title	Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
title_short	Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
title_full	Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
title_fullStr	Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
title_full_unstemmed	Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.
title_sort	virtual high-throughput screening identifies mycophenolic acid as a novel rna capping inhibitor.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/7835f4b3119543c9be163e02345e506a
work_keys_str_mv	AT maudetremblayletourneau virtualhighthroughputscreeningidentifiesmycophenolicacidasanovelrnacappinginhibitor AT simondespins virtualhighthroughputscreeningidentifiesmycophenolicacidasanovelrnacappinginhibitor AT isabellebougie virtualhighthroughputscreeningidentifiesmycophenolicacidasanovelrnacappinginhibitor AT martinbisaillon virtualhighthroughputscreeningidentifiesmycophenolicacidasanovelrnacappinginhibitor
_version_	1718445157156651008

Virtual high-throughput screening identifies mycophenolic acid as a novel RNA capping inhibitor.

Ejemplares similares