{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nQPCT encodes glutaminyl cyclase (QC), a zinc‐dependent enzyme that catalyzes the conversion of N‑terminal glutamine (or glutamate) residues into cyclic pyroglutamate on a wide variety of peptides and proteins. This posttranslational modification can profoundly affect peptide stability, resistance to aminopeptidase degradation, and aggregation propensity. Detailed structural studies and kinetic analyses have revealed that QC possesses a unique α/β scaffold with a relatively closed, metal‐coordinated active site. Key residues and a conserved hydrogen‐bond network assist in substrate binding and proton transfer during cyclization, and isoenzymes with distinct subcellular localizations (for example, Golgi‐resident forms) indicate that QC may act as part of a “housekeeping” protein maturation machinery."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nQC plays a critical role in neurodegenerative disease processes. In Alzheimer’s disease, for instance, QC‐catalyzed cyclization leads to the formation of pyroglutamate‐modified amyloid‑β peptides that exhibit enhanced resistance to degradation, altered aggregation dynamics, and increased neurotoxicity. Similar mechanisms have been implicated in the processing of N‑terminal fragments of other neuropeptides—for example, a glutamine‐initiated fragment of α‑synuclein contributing to Parkinson’s pathology. Elevated QC expression in select brain regions correlates with the deposition of these modified peptides and clinical severity, and structural insights have facilitated efforts to design specific QC inhibitors as a therapeutic strategy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established role in neurodegeneration, QC has been implicated in a number of other pathophysiological contexts. Genetic variations in QPCT are associated with altered bone mineral density and osteoporosis risk, while polymorphism studies have linked QPCT with blood pressure regulation. In cancer, for example, QC‐mediated formation of pyroglutamate residues on chemokines (such as CCL2) appears to modulate tumor cell migration and metastasis in thyroid carcinomas, and aberrant QC activity may contribute to drug resistance in renal cell carcinoma. Moreover, associations with schizophrenia further underscore the enzyme’s multifaceted impact on human health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvances in recombinant expression systems and high‐resolution structural investigations have not only deepened our understanding of QC’s catalytic mechanism but have also paved the way for rational inhibitor design and the exploration of QC as a novel biomarker. Heterologous expression studies confirm that QC’s proper folding, glycosylation, and disulfide bonding are essential for enzymatic activity, while computational and crystallographic analyses continue to refine our model of its active site. These multifaceted insights underscore QC’s importance as both a physiological modulator in peptide maturation and a promising target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephan Schilling, Torsten Hoffmann, Fred Rosche, et al. 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Potent inhibition by imidazole derivatives and heterocyclic chelators."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M309077200"}], "href": "https://doi.org/10.1074/jbc.M309077200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14522962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14522962"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kai-Fa Huang, Yi-Liang Liu, Wei-Ju Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0504184102"}], "href": "https://doi.org/10.1073/pnas.0504184102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16135565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16135565"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kai-Fa Huang, Yu-Ruei Wang, En-Cheng Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A conserved hydrogen-bond network in the catalytic centre of animal glutaminyl cyclases is critical for catalysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20071073"}], "href": "https://doi.org/10.1042/BJ20071073"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18072935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18072935"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Matteo Calvaresi, Marco Garavelli, Andrea Bottoni "}, {"type": "b", "children": [{"type": "t", "text": "Computational evidence for the catalytic mechanism of glutaminyl cyclase. A DFT investigation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proteins (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/prot.22061"}], "href": "https://doi.org/10.1002/prot.22061"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18470930"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18470930"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Holger Cynis, Jens-Ulrich Rahfeld, Anett Stephan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2008.03.078"}], "href": "https://doi.org/10.1016/j.jmb.2008.03.078"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18486145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18486145"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kai-Fa Huang, Jing-Siou Huang, Mao-Lun Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Unique Carboxylic-Acid Hydrogen-Bond Network (CAHBN) Confers Glutaminyl Cyclase Activity on M28 Family Enzymes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2021.166960"}], "href": "https://doi.org/10.1016/j.jmb.2021.166960"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33774034"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33774034"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Markus Morawski, Maike Hartlage-Rübsamen, Carsten Jäger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00401-010-0685-y"}], "href": "https://doi.org/10.1007/s00401-010-0685-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20383514"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20383514"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kai-Fa Huang, Su-Sen Liaw, Wei-Lin Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.208595"}], "href": "https://doi.org/10.1074/jbc.M110.208595"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21288892"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21288892"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Maike Hartlage-Rübsamen, Markus Morawski, Alexander Waniek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00401-011-0806-2"}], "href": "https://doi.org/10.1007/s00401-011-0806-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21301857"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21301857"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Maria Teresa Valenti, Silvia Bolognin, Cristina Zanatta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased glutaminyl cyclase expression in peripheral blood of Alzheimer's disease patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-120517"}], "href": "https://doi.org/10.3233/JAD-120517"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23207485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23207485"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Markus Morawski, Stephan Schilling, Moritz Kreuzberger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glutaminyl cyclase in human cortex: correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-131535"}], "href": "https://doi.org/10.3233/JAD-131535"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24164736"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24164736"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Claire Bridel, Torsten Hoffmann, Antje Meyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glutaminyl cyclase activity correlates with levels of Aβ peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer's disease patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alzheimers Res Ther (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13195-017-0266-6"}], "href": "https://doi.org/10.1186/s13195-017-0266-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28587659"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28587659"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Oliver Kupski, Lisa-Marie Funk, Viktor Sautner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer's Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.biochem.0c00337"}], "href": "https://doi.org/10.1021/acs.biochem.0c00337"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32551535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32551535"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Maike Hartlage-Rübsamen, Alexandra Bluhm, Sandra Moceri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00401-021-02349-5"}], "href": "https://doi.org/10.1007/s00401-021-02349-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34309760"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34309760"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yoichi Ezura, Mitsuko Kajita, Ryota Ishida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene (QPCT) with low radial BMD in adult women."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1359/JBMR.040324"}], "href": "https://doi.org/10.1359/JBMR.040324"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15231017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15231017"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yoshiji Yamada, Fujiko Ando, Hiroshi Shimokata "}, {"type": "b", "children": [{"type": "t", "text": "Association of gene polymorphisms with blood pressure and the prevalence of hypertension in community-dwelling Japanese individuals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17334644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17334644"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Qing-Yang Huang, Annie W C Kung "}, {"type": "b", "children": [{"type": "t", "text": "The association of common polymorphisms in the QPCT gene with bone mineral density in the Chinese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10038-007-0178-6"}], "href": "https://doi.org/10.1007/s10038-007-0178-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17687619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17687619"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Qiao-Quan Zhang, Teng Jiang, Li-Ze Gu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common Polymorphisms Within QPCT Gene Are Associated with the Susceptibility of Schizophrenia in a Han Chinese Population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-015-9541-3"}], "href": "https://doi.org/10.1007/s12035-015-9541-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26572640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26572640"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Tangliang Zhao, Yulin Zhou, Qingyun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijo.2021.5228"}], "href": "https://doi.org/10.3892/ijo.2021.5228"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34036385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34036385"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Tairong Liang, Xiuqian Wu, Lan Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical significance and diagnostic value of QPCT, SCEL and TNFRSF12A in papillary thyroid cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2023.154431"}], "href": "https://doi.org/10.1016/j.prp.2023.154431"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37060824"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37060824"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Lulu Liu, Haihui Liu, Lei Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apicidin confers promising therapeutic effect on acute myeloid leukemia cells via increasing QPCT expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2023.2228497"}], "href": "https://doi.org/10.1080/15384047.2023.2228497"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37381175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37381175"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Rachell E Booth, Stephanie A Misquitta, Robert C Bateman "}, {"type": "b", "children": [{"type": "t", "text": "Human pituitary glutaminyl cyclase: expression in insect cells and dye affinity purification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Expr Purif (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S1046-5928(03)00226-2"}], "href": "https://doi.org/10.1016/S1046-5928(03"}, {"type": "t", "text": "00226-2) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14680951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14680951"}]}]}]}