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Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC

Stable NAD(+) analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD(+)‐consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity...

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Autores principales: Madern, Jerre M., Kim, Robbert Q., Misra, Mohit, Dikic, Ivan, Zhang, Yong, Ovaa, Huib, Codée, Jeroen D. C., Filippov, Dmitri V., van der Heden van Noort, Gerbrand J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687180/
https://www.ncbi.nlm.nih.gov/pubmed/32421893
http://dx.doi.org/10.1002/cbic.202000230
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author Madern, Jerre M.
Kim, Robbert Q.
Misra, Mohit
Dikic, Ivan
Zhang, Yong
Ovaa, Huib
Codée, Jeroen D. C.
Filippov, Dmitri V.
van der Heden van Noort, Gerbrand J.
author_facet Madern, Jerre M.
Kim, Robbert Q.
Misra, Mohit
Dikic, Ivan
Zhang, Yong
Ovaa, Huib
Codée, Jeroen D. C.
Filippov, Dmitri V.
van der Heden van Noort, Gerbrand J.
author_sort Madern, Jerre M.
collection PubMed
description Stable NAD(+) analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD(+)‐consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity of the Legionella SdeC enzyme, we prepared three NAD(+) analogues, namely carbanicotinamide adenosine dinucleotide (c‐NAD(+)), thionicotinamide adenosine dinucleotide (S‐NAD(+)) and benzamide adenosine dinucleotide (BAD). We optimized the chemical synthesis of thionicotinamide riboside and for the first time used an enzymatic approach to convert all three ribosides into the corresponding NAD(+) mimics. We thus expanded the known scope of substrates for the NRK1/NMNAT1 enzyme combination by turning all three modified ribosides into NAD(+) analogues in a scalable manner. We then compared the three NAD(+) mimics side‐by‐side in a single assay for enzyme inhibition on Legionella effector enzyme SdeC. The class of SidE enzymes to which SdeC belongs was recently identified to be important in bacterial virulence, and we found SdeC to be inhibited by S‐NAD(+) and BAD with IC(50) values of 28 and 39 μM, respectively.
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spelling pubmed-76871802020-12-05 Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC Madern, Jerre M. Kim, Robbert Q. Misra, Mohit Dikic, Ivan Zhang, Yong Ovaa, Huib Codée, Jeroen D. C. Filippov, Dmitri V. van der Heden van Noort, Gerbrand J. Chembiochem Communications Stable NAD(+) analogues carrying single atom substitutions in either the furanose ring or the nicotinamide part have proven their value as inhibitors for NAD(+)‐consuming enzymes. To investigate the potential of such compounds to inhibit the adenosine diphosphate ribosyl (ADPr) transferase activity of the Legionella SdeC enzyme, we prepared three NAD(+) analogues, namely carbanicotinamide adenosine dinucleotide (c‐NAD(+)), thionicotinamide adenosine dinucleotide (S‐NAD(+)) and benzamide adenosine dinucleotide (BAD). We optimized the chemical synthesis of thionicotinamide riboside and for the first time used an enzymatic approach to convert all three ribosides into the corresponding NAD(+) mimics. We thus expanded the known scope of substrates for the NRK1/NMNAT1 enzyme combination by turning all three modified ribosides into NAD(+) analogues in a scalable manner. We then compared the three NAD(+) mimics side‐by‐side in a single assay for enzyme inhibition on Legionella effector enzyme SdeC. The class of SidE enzymes to which SdeC belongs was recently identified to be important in bacterial virulence, and we found SdeC to be inhibited by S‐NAD(+) and BAD with IC(50) values of 28 and 39 μM, respectively. John Wiley and Sons Inc. 2020-06-16 2020-10-15 /pmc/articles/PMC7687180/ /pubmed/32421893 http://dx.doi.org/10.1002/cbic.202000230 Text en © 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Communications
Madern, Jerre M.
Kim, Robbert Q.
Misra, Mohit
Dikic, Ivan
Zhang, Yong
Ovaa, Huib
Codée, Jeroen D. C.
Filippov, Dmitri V.
van der Heden van Noort, Gerbrand J.
Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title_full Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title_fullStr Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title_full_unstemmed Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title_short Synthesis of Stable NAD(+) Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC
title_sort synthesis of stable nad(+) mimics as inhibitors for the legionella pneumophila phosphoribosyl ubiquitylating enzyme sdec
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687180/
https://www.ncbi.nlm.nih.gov/pubmed/32421893
http://dx.doi.org/10.1002/cbic.202000230
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