Novel Quinic Acid Glycerates from Tussilago farfara Inhibit Polypeptide GalNAc-Transferase.
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemistry
Flowers
/ chemistry
Glycosylation
HEK293 Cells
Humans
Molecular Conformation
N-Acetylgalactosaminyltransferases
/ antagonists & inhibitors
Quinic Acid
/ chemistry
Structure-Activity Relationship
Tussilago
/ chemistry
Polypeptide N-acetylgalactosaminyltransferase
GalNAc-Ts
drug discovery
genome editing
inhibitors
natural products
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
04 02 2022
04 02 2022
Historique:
revised:
30
11
2021
received:
08
10
2021
pubmed:
2
12
2021
medline:
9
3
2022
entrez:
1
12
2021
Statut:
ppublish
Résumé
The discovery of a bioactive inhibitor tool for human polypeptide N-acetylgalactosaminyl transferases (GalNAc-Ts), the initiating enzyme for mucin-type O-glycosylation, remains challenging. In the present study, we identified an array of quinic acid derivatives, including four new glycerates (1-4) from Tussilago farfara, a traditional Chinese medicinal plant, as active inhibitors of GalNAc-T2 using a combined screening approach with a cell-based T2-specific sensor and purified enzyme assay. These inhibitors dose-dependently inhibited human GalNAc-T2 but did not affect O-linked N-acetylglucosamine transferase (OGT), the other type of glycosyltransferase. Importantly, they are not cytotoxic and retain inhibitory activity in cells lacking elongated O-glycans, which are eliminated by the CRISPR/Cas9 gene editing tool. A structure-activity relationship study unveiled a novel quinic acid-caffeic acid conjugate pharmacophore that directs inhibition. Overall, these new natural product inhibitors could serve as a basis for developing an inhibitor tool for GalNAc-T2.
Identifiants
pubmed: 34850523
doi: 10.1002/cbic.202100539
doi:
Substances chimiques
Enzyme Inhibitors
0
Quinic Acid
058C04BGYI
N-Acetylgalactosaminyltransferases
EC 2.4.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202100539Subventions
Organisme : National Natural Science Foundation of China
ID : 31870763
Organisme : Natural Science Foundation of Shandong Province
ID : JQ201721
Organisme : Shanghai Foundation for the Development of Science and Technology
ID : 19JC1413000
Organisme : Research Fund of Medicine and Engineering of Shanghai Jiao Tong University
ID : YG2019QNB27
Organisme : Research Fund of Medicine and Engineering of Shanghai Jiao Tong University
ID : YG2021QN144
Organisme : Department of Biological Sciences, Carnegie Mellon University
Informations de copyright
© 2021 Wiley-VCH GmbH.
Références
E. P. Bennett, U. Mandel, H. Clausen, T. A. Gerken, T. A. Fritz, L. A. Tabak, Glycobiology 2011, 22, 736-756.
H. J. Joshi, Y. Narimatsu, K. T. Schjoldager, H. L. Tytgat, M. Aebi, H. Clausen, A. Halim, Cell 2018, 172, 632-632, e632;
D. J. Gill, H. Clausen, F. Bard, Trends Cell Biol. 2011, 21, 149-158.
Y. Hu, J. Feng, F. Wu, ChemBioChem 2018, 19, 2503-2521.
T.-B. S. Katrine, M. B. Vester-Christensen, E. P. Bennett, S. B. Levery, T. Schwientek, W. Yin, O. Blixt, H. Clausen, J. Biol. Chem. 2010, 285, 36293-36303;
L. Song, C. Bachert, K. T. Schjoldager, H. Clausen, A. D. Linstedt, J. Biol. Chem. 2014, 289, 30556-30566.
K. Kato, C. Jeanneau, M. A. Tarp, A. Benet-Pagès, B. Lorenz-Depiereux, E. P. Bennett, U. Mandel, T. M. Strom, H. Clausen, J. Biol. Chem. 2006, 281, 18370-18377;
L. Song, A. D. Linstedt, eLife 2017, 6, e24051.
A. Weidemann, G. König, D. Bunke, P. Fischer, J. M. Salbaum, C. L. Masters, K. Beyreuther, Cell 1989, 57, 115-126;
S. Kitazume, Y. Tachida, M. Kato, Y. Yamaguchi, T. Honda, Y. Hashimoto, Y. Wada, T. Saito, N. Iwata, T. Saido, J. Biol. Chem. 2010, 285, 40097-40103.
S. A. Khetarpal, K. T. Schjoldager, C. Christoffersen, A. Raghavan, A. C. Edmondson, H. M. Reutter, B. Ahmed, R. Ouazzani, G. M. Peloso, C. Vitali, Cell Metab. 2016, 24, 234-245;
A. G. Holleboom, H. Karlsson, R.-S. Lin, T. M. Beres, J. A. Sierts, D. S. Herman, E. S. Stroes, J. M. Aerts, J. J. Kastelein, M. M. Motazacker, Cell Metab. 2011, 14, 811-818.
A. Mullard, Nat. Rev. Drug Discovery 2021, 20, 251.
US. Food & Drug. Administration, Retrieved from FDA. gov: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-rare-inherited-form-rickets-x-linked-hypophosphatemia2018.
K. Servick, Science 2021, 372, 1141.
F. Liu, K. Xu, Z. Xu, M. de las Rivas, C. Wang, X. Li, J. Lu, Y. Zhou, I. Delso, P. Merino, R. Hurtado-Guerrero, Y. Zhang, F. Wu, J. Biol. Chem. 2017, 292, 21304-21319.
C. Steentoft, S. Y. Vakhrushev, H. J. Joshi, Y. Kong, M. B. Vester-Christensen, K. T. B. Schjoldager, K. Lavrsen, S. Dabelsteen, N. B. Pedersen, L. Marcos-Silva, EMBO J. 2013, 32, 1478-1488.
E. J. Lee, J. S. Kim, H. P. Kim, J.-H. Lee, S. S. Kang, Food Chem. 2010, 120, 134-139.
J. Chen, S. Mangelinckx, L. Ma, Z. Wang, W. Li, N. De Kimpe, Fitoterapia 2014, 99, 1-6.
X. Zhu, X. Dong, Y. Wang, P. Ju, S. Luo, Helv. Chim. Acta 2005, 88, 339-342.
G. Huet, I. Kim, C. De Bolos, J. Lo-Guidice, O. Moreau, B. Hemon, C. Richet, P. Delannoy, F. Real, P. Degand, J. Cell Sci. 1995, 108, 1275-1285.
Y. Wang, T. Ju, X. Ding, B. Xia, W. Wang, L. Xia, M. He, R. D. Cummings, Proc. Natl. Acad. Sci. USA 2010, 107, 9228-9233.
T. Ju, R. D. Cummings, Proc. Natl. Acad. Sci. USA 2002, 99, 16613-16618.
X.-Q. Song, J.-H. Yu, J. Sun, K.-L. Liu, J.-S. Zhang, H. Zhang, Bioorg. Chem. 2021, 107, 104632.
F. A. Ran, P. D. Hsu, J. Wright, V. Agarwala, D. A. Scott, F. Zhang, Nat. Protoc. 2013, 8, 2281-2308.
M. B. Lazarus, Y. Nam, J. Jiang, P. Sliz, S. Walker, Nature 2011, 469, 564.
L. Wang, H. Cai, Y. Hu, F. Liu, S. Huang, Y. Zhou, J. Yu, J. Xu, F. Wu, Cell Death Dis. 2018, 9, 1-17;
Y. Hu, L. Wang, X. Han, Y. Zhou, T. Zhang, L. Wang, T. Hong, W. Zhang, X.-X. Guo, J. Sun, J. Med. Chem. 2018, 62, 1677-1683.
G. Croppi, Y. Zhou, R. Yang, Y. Bian, M. Zhao, Y. Hu, B. H. Ruan, J. Yu, F. Wu, Cell Chem. Biol. 2020, 27, 1483-1499.
Y. Wang, J. Zhu, L. Zhang, J. Med. Chem. 2017, 60, 263-272.
J. L. Dahlin, K. M. Nelson, J. M. Strasser, D. Barsyte-Lovejoy, M. M. Szewczyk, S. Organ, M. Cuellar, G. Singh, J. H. Shrimp, N. Nguyen, Nat. Commun. 2017, 8, 1527.