2.3.2.5: glutaminyl-peptide cyclotransferase
This is an abbreviated version!
For detailed information about glutaminyl-peptide cyclotransferase, go to the full flat file.
Word Map on EC 2.3.2.5
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2.3.2.5
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pyroglutamate
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alzheimer
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cyclases
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pyroglutamyl
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papaya
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pyroglutamate-modified
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pglu-a
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medicine
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drug development
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antivenomics
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pharmacology
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n-truncated
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cd47-sirp
- 2.3.2.5
- pyroglutamate
- alzheimer
- cyclases
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pyroglutamyl
- papaya
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pyroglutamate-modified
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pglu-a
- medicine
- drug development
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antivenomics
- pharmacology
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n-truncated
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cd47-sirp
Reaction
Synonyms
AtQC, cyclotransferase, glutaminyl-transfer ribonucleate, DromeQC, gamma-glutamylamine cyclotransferase, GGACT, glutamine cyclotransferase, glutaminyl cyclase, glutaminyl-peptide cyclotransferase-like protein, glutaminyl-tRNA cyclotransferase, golgi resident enzyme, Golgi resident glutaminyl cyclase, Golgi-resident enzyme, Golgi-resident glutaminyl cyclase, gQC, h-isoQC, h-QC, hQC, isoDromeQC, isoGlutaminyl cyclase, isoQC, PgQC, QC, QCT, Qpct, Qpct1, QPCTL, secretory glutaminyl cyclase, sQC, StQC
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General Information
General Information on EC 2.3.2.5 - glutaminyl-peptide cyclotransferase
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evolution
malfunction
metabolism
physiological function
additional information
glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) belong to the family of the metalloenzymes
evolution
glutaminyl cyclase (QC, glutaminyl-peptide cyclotransferase (QPCT)) and its isoenzyme isoQC (QPCTL) belong to a family of enzymes which catalyze the formation of pyroglutamate (pGlu, pE) at N-terminus of proteins by converting glutamate/glutamine to pGlu residue
evolution
glutaminyl cyclases (QCs) belong to the class of acyl transferases. Different types of QCs are identified in bacteria, plants and animals, including mammalian tissues
knockdown of enzyme-transcript results in lower enzymatic activity, and small, unviable egg masses
malfunction
knockdown of enzyme-transcript results in lower enzymatic activity, and small, unviable egg masses
malfunction
glutaminyl cyclase inhibitors alter the CD47 protein by inhibiting QPCTL function and the resulting block in pGlu-modified CD47 is nearly complete. The expansion, differentiation, cytokine production and killing capacity of human T cells is compatible with small molecule inhibition of QPCTL. But QPCTL deficiency and QPCTL inhibition enhance tumor cell control by tumor-specific antibodies
malfunction
knockout of isoQC dramatically reduces the binding of SIRPalpha to cell surface
malfunction
loss of the pE-modification and N-terminal charge leads to accelerated aggregation of Abeta3(pE) compared with unmodified Abeta
evidence for an involvement of glutaminyl cyclase (QC) in Alzheimer's disease pathogenesis via QC-catalyzed pE-Abeta formation
metabolism
the activity of myeloid cells such as macrophages and neutrophils is likewise regulated by a balance between stimulatory and inhibitory signals. In particular, cell surface expression of the CD47 protein creates a 'don't eat me' signal on tumor cells by binding to SIRPalpha expressed on myeloid cells. CD47 is a broadly expressed inhibitory ligand for myeloid cells. The glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a major component of the CD47-SIRPalpha checkpoint. Interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo. Diglutamate formation occurs early in the CD47 protein life cycle and fully depends on QPCTL. Synergy between blockade of CD47 diglutamate formation and tumor opsonization in tumor cell killing by macrophages and neutrophils
metabolism
the dipeptidyl-peptidase activity of meprin beta links N-truncation of Abeta with glutaminyl cyclase-catalyzed pGlu-Abeta formation
metabolism
transmembrane protein CD47 is highly expressed on many types of cancer cells and can directly bind to the receptor signal regulatory protein alpha (SIRPalpha), which is highly expressed on phagocytic cells. Binding of CD47 to SIRPalpha can protect cancer cells from phagocytosis by phagocytic cells and therefore functions as the major 'don't eat me' signal. Therapeutic blockade of CD47-SIRPalpha axis can efficiently promote the macrophage-mediated phagocytosis and elimination of cancer cells. Glutaminyl cyclase isoenzyme isoQC is a regulator of SIRPalpha-CD47 axis
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glutaminyl cyclase contributes to the formation of focal and diffuse diglutamate-Abeta peptide deposits in hippocampus
physiological function
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glutaminyl cyclase contributes to the formation of focal and diffuse diglutamate-Abeta peptide deposits in hippocampus
physiological function
amyloid-beta peptide Abeta3-40/42 is the precursor of pGlu-Abeta3-40/42 generated by glutaminyl cyclase (QC). The formation of amyloid-beta (Abeta) peptides is causally involved in the development of Alzheimer's disease (AD)
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxin peptide sequences and classification, overview
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxxin peptide sequences and classification, overview
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxxin peptide sequences and classification, overview
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxxin peptide sequences and classification, overview
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxxin peptide sequences and classification, overview
physiological function
diglutamic acid (5-oxo-L-proline, pGlu, Z) formation at the N-terminus of proteins and peptides, a modification observed in both plant and animal kingdoms, requires the action of the enzyme glutaminyl cyclase (QC), which acts on amino terminus glutamine residues. The post-translational modification of N-terminal glutamine (Q) to a diglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Mass spectrometric analysis of toxxin peptide sequences and classification, overview
physiological function
glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into diglutamic acid (pGlu). The amyloid protein and the monocyte chemoattractant protein (MCP-1) also known as CCL2 that promotes a cascade of inflammation-related responses are two representative substrates. The diglutamated Abeta and CCL2 exhibit more severe neurotoxicity than normal Abeta and CCL2. The Abeta1-40/42 peptides start with an L-aspartate at the N-terminus. Under pathological conditions, the Abeta1-40/42 peptides are truncated to expose the glutamate at position 3 or 11 of the Abeta peptides. Then the N-terminal glutamate (E) will be cyclized by QC to form the pyroglutamate (pE) and the products are termed as Abeta3(pE)-40/42 or Abeta11(pE)-40/42. The pE-modification of Abeta confers unique properties, such as proteolytic resistance. pGlu-Abeta peptides exhibit enhanced toxicity compared to the unmodified Abeta peptide and promote the formation of tau tangles. In Alzheimer's disease (AD) patients and animal AD models, the level and activity of QC are significantly increased
physiological function
glutaminyl cyclase (QC) and isoglutaminyl cyclase (isoQC) catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into diglutamic acid (pGlu). The level of CCL2 and h-isoQCmRNA in Alzheimer disease (AD) patients is significantly higher than that of healthy subjects
physiological function
glutaminyl cyclase (QC) is one kind of acyltransferases, which catalyzes intramolecular cyclization of N-terminal glutamine residues to diglutamic acid (pGlu) with the concomitant liberation of ammonia. The post-translational formation of pGlu is an important process for the maturation of various bioactive neuropeptides, hormones, cytokines and for their biological activity, because the pGlu is required to protect the N termini from exopeptidase degradation and/or to develop the proper conformation. QC is abundant in mammalian secretory tissue such as secretory glands or brain tissue including hippocampus and cortex. Glutaminyl cyclase (QC) plays an important role in the initiation of the formation of neurotoxic plaques and in the pathogenesis of Alzheimer's disease (AD) due to the ability of human QC (hQC) to convert the N-terminal glutamate of beta-amyloids (Abetas) into respective pGlu-modified Abetas (pE-Abetas)
physiological function
glutaminyl cyclase activity correlates with levels of Abeta38, Abeta40 and angiogenesis mediators Flt1, Tie2, VEGFD, CAM-1 and ICAM-1 in cerebrospinal fluid of Alzheimers disease patients, core CSF diagnostic biomarkers (Abeta42, tau and p-tau) are not part of the diagnostic workup, detailed overview. Pyroglutamylation of truncated Abeta peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Abeta species with enhanced aggregation propensities and resistance to most amino-peptidases and endo-peptidases. pE-Abeta species have been identified as major constituents of Abeta plaques and reduction of pE-Abeta species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Some inflammatory or angiogenesis mediators are potential QC substrates
physiological function
glutaminyl cyclase isoenzyme isoQC is an essential regulator of CD47-SIRPalpha axis and required for efficient phagocytic cells-mediated clearance of cancer cells. N-terminal pGlu modification of proteins may protect protein from degradation by proteases or promote protein aggregation
physiological function
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glutaminyl cyclase synthesized by Porphyromonas gingivalis (PgQC) is a key pathogen in developing periodontitis, potential link of periodontitis with rheumatoid arthritis (RA)
physiological function
glutaminyl cyclases (QCs) catalyze the intramolecular cyclization of N-terminal L-glutamine residues of peptides and proteins into pyroglutamic acid (5-oxo-prolyl, pGlu, pE) releasing ammonia, as well as the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid. Such a type of post-translational modification stabilizes the peptides and proteins, protects them from proteolytic degradation, and can be important for their biological activity
physiological function
human glutaminyl cyclase (hQC) is an important enzyme for post-translational modification by converting the N-terminal glutaminyl and glutamyl into diglutamate (pGlu) through cyclization. The two isoforms of hQC, secretory glutaminyl cyclase (sQC) and Golgi resident glutaminyl cyclase (gQC), are involved in various pathological conditions especially in Alzheimer's disease (AD). The sQC is known to mediate the formation of diglutamate containing amyloid beta (pGlu-Abeta) peptides while gQC mediates the maturation of C-C motif chemokine ligand 2 (CCL2)
physiological function
the enzyme glutaminyl cyclase (QC) acts as glutamyl cyclase to catalyze pE-Abeta formation from N-terminal glutamate. A glutamate residue (E) is exposed at position 3 of Abeta(3-42) and can be converted by the enzymatic activity of glutaminyl cyclase (QC) to pE resulting in the peptide pE-Abeta(3-42). Slow conversion of N-terminal glutamate under slightly acidic pH conditions, as compared with the much faster pE formation from N-terminal glutamine
physiological function
the glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a Golgi-resident enzyme that, like its secreted family member QPCT, can catalyze the cyclization of N-terminal glutamine and glutamic acid residues on target proteins into an N-terminal pyroglutamate residue (pGlu). QPCTL is a major component of the CD47-SIRPalpha checkpoint. Diglutamate formation occurs early in the CD47 protein life cycle and fully depends on QPCTL. QPCTL is critical for diglutamate formation on CD47 at the SIRPalpha binding site shortly after biosynthesis. QPCTL is a modulator of CD47-SIRPalpha binding. Genetic and pharmacological interference with QPCTL activity enhances antibody-dependent cellular phagocytosis and cellular cytotoxicity of tumor cells. Interference with QPCTL expression leads to a major increase in neutrophil-mediated killing of tumor cells in vivo
active site structure of gQC, residue W231 in gQC has adopted an outward positioning of the indole ring and is involved in hydrogen bonding with one of the neighboring amino acid P256. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Catalytic reaction mechanism
additional information
active site structure of gQC, residue W231 in gQC has adopted an outward positioning of the indole ring and is involved in hydrogen bonding with one of the neighboring amino acid P256. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Catalytic reaction mechanism
additional information
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active site structure of gQC, residue W231 in gQC has adopted an outward positioning of the indole ring and is involved in hydrogen bonding with one of the neighboring amino acid P256. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Catalytic reaction mechanism
additional information
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enzyme expression analysis in Porphyromonas gingivalis on patients with chronic periodontitis (CP) and rheumatoid arthritis (RA), overview
additional information
two active site conformations are reported for sQC (Conf-A and Conf-B) and these are mainly associated with the orientation of W207. In Conf-A (open), the orientation of the indole ring of W207 is towards the surface of the molecule and in Conf-B (closed), the orientation is towards the Zn2+ ion. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Residues C139 and C164 are not involved in catalysis. Catalytic reaction mechanism
additional information
two active site conformations are reported for sQC (Conf-A and Conf-B) and these are mainly associated with the orientation of W207. In Conf-A (open), the orientation of the indole ring of W207 is towards the surface of the molecule and in Conf-B (closed), the orientation is towards the Zn2+ ion. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Residues C139 and C164 are not involved in catalysis. Catalytic reaction mechanism
additional information
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two active site conformations are reported for sQC (Conf-A and Conf-B) and these are mainly associated with the orientation of W207. In Conf-A (open), the orientation of the indole ring of W207 is towards the surface of the molecule and in Conf-B (closed), the orientation is towards the Zn2+ ion. Substrate binding and structural analysis, detailed overview. In both QC isozymes, three acidic residues (E201, D248, and D305 in sQC, and E225, D269 and D326 in gQC) are pointed to each other and are likely to form hydrogen bonds between them. These residues play a major role in the catalysis. Residues C139 and C164 are not involved in catalysis. Catalytic reaction mechanism