| Structural highlights
Function
QPCT_HUMAN Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.[1] [2] [3]
Publication Abstract from PubMed
Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Abeta, which acts as a potential seed for the aggregation of full length Abeta. Preventing the formation of pGlu-Abeta through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC50 = 34 muM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors.
Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors.,Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, Sivaraman DM, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ Int J Biol Macromol. 2020 Dec 27;170:415-423. doi:, 10.1016/j.ijbiomac.2020.12.118. PMID:33373636[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004 Apr 9;563(1-3):191-6. PMID:15063747 doi:http://dx.doi.org/10.1016/S0014-5793(04)00300-X
- ↑ Cynis H, Rahfeld JU, Stephan A, Kehlen A, Koch B, Wermann M, Demuth HU, Schilling S. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J Mol Biol. 2008 Jun 20;379(5):966-80. doi: 10.1016/j.jmb.2008.03.078. Epub 2008 , Apr 15. PMID:18486145 doi:http://dx.doi.org/10.1016/j.jmb.2008.03.078
- ↑ Huang KF, Liaw SS, Huang WL, Chia CY, Lo YC, Chen YL, Wang AH. Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding. J Biol Chem. 2011 Apr 8;286(14):12439-49. Epub 2011 Feb 1. PMID:21288892 doi:10.1074/jbc.M110.208595
- ↑ Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, Sivaraman DM, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. Int J Biol Macromol. 2020 Dec 27;170:415-423. doi:, 10.1016/j.ijbiomac.2020.12.118. PMID:33373636 doi:http://dx.doi.org/10.1016/j.ijbiomac.2020.12.118
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