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Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)

Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an inter...

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Autores principales: van Haren, Matthijs J., Zhang, Yurui, Thijssen, Vito, Buijs, Ned, Gao, Yongzhi, Mateuszuk, Lukasz, Fedak, Filip A., Kij, Agnieszka, Campagna, Roberto, Sartini, Davide, Emanuelli, Monica, Chlopicki, Stefan, Jongkees, Seino A. K., Martin, Nathaniel I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496086/
https://www.ncbi.nlm.nih.gov/pubmed/34704059
http://dx.doi.org/10.1039/d1cb00134e
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author van Haren, Matthijs J.
Zhang, Yurui
Thijssen, Vito
Buijs, Ned
Gao, Yongzhi
Mateuszuk, Lukasz
Fedak, Filip A.
Kij, Agnieszka
Campagna, Roberto
Sartini, Davide
Emanuelli, Monica
Chlopicki, Stefan
Jongkees, Seino A. K.
Martin, Nathaniel I.
author_facet van Haren, Matthijs J.
Zhang, Yurui
Thijssen, Vito
Buijs, Ned
Gao, Yongzhi
Mateuszuk, Lukasz
Fedak, Filip A.
Kij, Agnieszka
Campagna, Roberto
Sartini, Davide
Emanuelli, Monica
Chlopicki, Stefan
Jongkees, Seino A. K.
Martin, Nathaniel I.
author_sort van Haren, Matthijs J.
collection PubMed
description Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In the search for structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC(50) values as low as 229 nM. The peptides were also found to downregulate MNA production in cellular assays. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT.
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spelling pubmed-84960862021-10-25 Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT) van Haren, Matthijs J. Zhang, Yurui Thijssen, Vito Buijs, Ned Gao, Yongzhi Mateuszuk, Lukasz Fedak, Filip A. Kij, Agnieszka Campagna, Roberto Sartini, Davide Emanuelli, Monica Chlopicki, Stefan Jongkees, Seino A. K. Martin, Nathaniel I. RSC Chem Biol Chemistry Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S-adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In the search for structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC(50) values as low as 229 nM. The peptides were also found to downregulate MNA production in cellular assays. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT. RSC 2021-08-19 /pmc/articles/PMC8496086/ /pubmed/34704059 http://dx.doi.org/10.1039/d1cb00134e Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
van Haren, Matthijs J.
Zhang, Yurui
Thijssen, Vito
Buijs, Ned
Gao, Yongzhi
Mateuszuk, Lukasz
Fedak, Filip A.
Kij, Agnieszka
Campagna, Roberto
Sartini, Davide
Emanuelli, Monica
Chlopicki, Stefan
Jongkees, Seino A. K.
Martin, Nathaniel I.
Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title_full Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title_fullStr Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title_full_unstemmed Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title_short Macrocyclic peptides as allosteric inhibitors of nicotinamide N-methyltransferase (NNMT)
title_sort macrocyclic peptides as allosteric inhibitors of nicotinamide n-methyltransferase (nnmt)
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496086/
https://www.ncbi.nlm.nih.gov/pubmed/34704059
http://dx.doi.org/10.1039/d1cb00134e
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