Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors

2021 ◽  
Author(s):  
Chenshu Xu ◽  
Yi-nan Wang ◽  
Haiqiang Wu
Keyword(s):  
Glutaminyl Cyclase

Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene QPC with low radial BMD in adult women.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Linkage Disequilibrium ◽  
Multiple Regression ◽  
Genetic Variations ◽  
Strong Linkage Disequilibrium ◽  
Adult Women ◽  
Nucleotide Polymorphisms ◽  
Haplotype Estimation ◽  
Factors Affecting ◽  
Glutaminyl Cyclase ◽  
Strong Linkage

Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene andadjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium,R54W showed a prominent association (p ? 0.0003), which was more striking when examined among 309 eldersubjects (>50 years; p ? 0.0001). Contribution for postmenopausal bone loss was suggested.Introduction: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis(HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have beenproposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene(GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essentialmodifier of pituitary peptide hormones, including GnRH.Materials and Methods: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locuswith adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) wasanalyzed by haplotype estimation and calculation of D? and r2. Multiple regression analysis was applied forevaluating the combined effects of the variations.Results and Conclusions: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of theQPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD,among which R54W (nt ? 160C?T) presented the most prominent association (p ? 0.0003). Striking associationwas observed for these SNPs among the 309 subjects ?50 years of age (R54W, p ? 0.0001; ?1095T?C, p ?0.0002; ?1844C?T, p ? 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might actin combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are theimportant factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The datashould provide new insight into the etiology of the disease and may suggest a new target to be considered duringtreatment.J Bone Miner

scholarly journals A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

2021 ◽  
Author(s):  
Maike Hartlage-Rübsamen ◽  
Alexandra Bluhm ◽  
Sandra Moceri ◽  
Lisa Machner ◽  
Janett Köppen ◽  
...  
Keyword(s):  
Cell Viability ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Size Exclusion ◽  
Lewy Neurites ◽  
Enzymatic Assays ◽  
Aβ Peptides ◽  
Glutaminyl Cyclase ◽  
Affect Cell Viability ◽  
Exclusion Chromatography

AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.

Glutaminyl cyclase activity is a characteristic feature of human cerebrospinal fluid

2008 ◽  
Vol 389 (1-2) ◽  
pp. 152-159 ◽  
Author(s):  
Anastassia Gontsarova ◽  
Eckhard Kaufmann ◽  
Hayrettin Tumani ◽  
Alexander Dressel ◽  
Friedrich Mandel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Characteristic Feature ◽  
Cyclase Activity ◽  
Glutaminyl Cyclase ◽  
Human Cerebrospinal Fluid

scholarly journals Identification of Human Glutaminyl Cyclase as a Metalloenzyme

2003 ◽  
Vol 278 (50) ◽  
pp. 49773-49779 ◽  
Author(s):  
Stephan Schilling ◽  
André J. Niestroj ◽  
Jens-Ulrich Rahfeld ◽  
Torsten Hoffmann ◽  
Michael Wermann ◽  
...  
Keyword(s):  
Glutaminyl Cyclase

scholarly journals Pyroglutamate-Amyloid-� and Glutaminyl Cyclase Are Colocalized with Amyloid-� in Secretory Vesicles and Undergo Activity-Dependent, Regulated Secretion

2014 ◽  
Vol 14 (2) ◽  
pp. 85-97 ◽  
Author(s):  
Holger Cynis ◽  
Lydiane Funkelstein ◽  
Thomas Toneff ◽  
Charles Mosier ◽  
Michael Ziegler ◽  
...  
Keyword(s):  
Secretory Vesicles ◽  
Glutaminyl Cyclase ◽  
Regulated Secretion ◽  
Activity Dependent

scholarly journals Primary structure and functional expression of a glutaminyl cyclase.

1991 ◽  
Vol 88 (22) ◽  
pp. 10059-10063 ◽  
Author(s):  
T. Pohl ◽  
M. Zimmer ◽  
K. Mugele ◽  
J. Spiess
Keyword(s):  
Primary Structure ◽  
Functional Expression ◽  
Glutaminyl Cyclase

scholarly journals N-terminal pyroglutamate formation in CX3CL1 is essential for its full biologic activity

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Astrid Kehlen ◽  
Monique Haegele ◽  
Livia Böhme ◽  
Holger Cynis ◽  
Torsten Hoffmann ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Adhesion Molecule ◽  
Muscle Cells ◽  
Mitogen Activated Protein Kinase ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Glutaminyl Cyclase ◽  
N Terminus

CX3CL1 (fractalkine) is a unique member of the CX3C chemokine family and mediates both adhesion and cell migration in inflammatory processes. Frequently, the activity of chemokines depends on a modified N-terminus as described for the N-terminus of CCL2 modified to a pGlu- (pyroglutamate) residue by QC (glutaminyl cyclase) activity. Here, we assess the role of the pGlu-modified residue of the CX3CL1 chemokine domain in human endothelial and smooth muscle cells. For the first time, we demonstrated using MS that QC (QPCT, gene name of QC) or its isoenzyme isoQC (iso-glutaminyl cyclase) (QPCTL, gene name of isoQC) catalyse the formation of N-terminal-modified pGlu-CX3CL1. Expression of QPCT is co-regulated with its substrates CCL2 and CX3CL1 in HUVECs (human umbilical vein endothelial cells) and HCASMCs (human coronary artery smooth muscle cells) upon stimulation with TNF-α and IL-1β whereas QPCTL expression is not affected. By contrast, inhibition of the NF-κB pathway using an IKK2 inhibitor decreased the expression of the co-regulated targets QPCT, CCL2, and CX3CL1. Furthermore, RNAi-mediated inhibition of QPCT expression resulted in a reduction in CCL2 and CX3CL1 mRNA. In HCASMCs, N-terminal-modified pGlu1-CX3CL1 induced a significant stronger effect on phosphorylation of ERK (extracellular signal regulated kinase) 1/2, Akt (protein kinase B), and p38 (p38 mitogen-activated protein kinase) kinases than the immature Gln1-CX3CL1 in a time- and concentration-dependent manner. Furthermore, pGlu1-CX3CL1 affected the expression of CCL2, CX3CL1, and the adhesion molecule ICAM1/CD54 (intercellular adhesion molecule-1) inducing in higher expression level compared with its Gln1-variant in both HCASMCs and HUVECs. These results strongly suggest that QC-catalysed N-terminal pGlu formation of CX3CL1 is important for the stability or the interaction with its receptor and opens new insights into the function of QC in inflammation.

P3-031: New mouse model to develop and test drugs against the human Glutaminyl Cyclase (hQC) for Alzheimer's disease research

2011 ◽  
Vol 7 ◽  
pp. S524-S524
Author(s):  
Annamaria Molnar ◽  
Stephan Kurat ◽  
Stephan Schilling ◽  
Stefanie Flunkert ◽  
Hans Demuth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Glutaminyl Cyclase ◽  
Disease Research

Crystal Structure of Papaya Glutaminyl Cyclase, an Archetype for Plant and Bacterial Glutaminyl Cyclases

2006 ◽  
Vol 357 (2) ◽  
pp. 457-470 ◽  
Author(s):  
René Wintjens ◽  
Hassan Belrhali ◽  
Bernard Clantin ◽  
Mohamed Azarkan ◽  
Coralie Bompard ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Glutaminyl Cyclase
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