Cargando…
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...
Autores principales: | , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784579687353155584 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8496086 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | RSC |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT vanharenmatthijsj macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT zhangyurui macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT thijssenvito macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT buijsned macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT gaoyongzhi macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT mateuszuklukasz macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT fedakfilipa macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT kijagnieszka macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT campagnaroberto macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT sartinidavide macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT emanuellimonica macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT chlopickistefan macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT jongkeesseinoak macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt AT martinnathanieli macrocyclicpeptidesasallostericinhibitorsofnicotinamidenmethyltransferasennmt |