The post-translational modification of N-terminal glutamine (Q) to a pyroglutamyl (Z) residue is observed in the conotoxins produced by marine cone snails. This conversion requires the action of the enzyme glutaminyl cyclase (QC). Four complete QC sequences from the species C. araneosus, C. frigidus, C. litteratus, and C. monile and two partial sequences from C. amadis and C. miles have been obtained by analysis of transcriptomic data. Comparisons with mammalian enzyme sequences establish a high level of identity and complete conservation of functional active site residues, including a cluster of hydrogen-bonded acidic side chains. Mass spectrometric analysis of crude venom samples coupled to conotoxin precursor protein sequences obtained from transcriptomic data establishes the presence of pyroglutamyl conotoxins in the venom of C. frigidus and C. amadis. The C. frigidus peptide belongs to the M superfamily, with cysteine framework III, whereas the C. amadis peptide belongs to the divergent superfamily with cysteine framework VI/VII. Additionally, gamma carboxylation of glutamic acid and hydroxylation of proline are observed in the C. frigidus peptide. Mass spectral data are available via ProteomeXchange with identifier PXD009006.
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http://dx.doi.org/10.1021/acs.jproteome.8b00132 | DOI Listing |
J Med Chem
January 2025
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Glutaminyl cyclases, including glutaminyl-peptide cyclotransferase (QPCT) and glutaminyl-peptide cyclotransferase-like protein (QPCTL), primarily catalyze the cyclization of N-terminal glutamine or glutamate to pyroglutamate (pGlu). QPCTL, in particular, modifies the N-terminus of CD47, thereby regulating its interaction with signal-regulatory protein alpha (SIRPα) and modulating phagocytosis of tumor cells by immune cells. Additionally, QPCTL cyclizes the N-termini of CCL2, CCL7, and CX3CL1, influencing the tumor microenvironment and inflammatory responses in cancer and other disorders.
View Article and Find Full Text PDFInt J Biol Macromol
December 2024
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. Electronic address:
The formation of the pyroglutamate variant of amyloid beta (pGlu-Aβ), which is extremely hydrophobic, rapidly aggregating, and highly neurotoxic, is mediated by the action of secretory glutaminyl cyclase (sQC). The pGlu-Aβ often acts as a seed for the aggregation of the full length Aβ and contributes to the overall load of Aβ plaques in Alzheimer's disease (AD). Therefore, inhibiting sQC is a potential approach to limit the formation of pGlu-Aβ and to modify the progression of AD.
View Article and Find Full Text PDFGene
February 2025
Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India.
Glutaminyl-peptide cyclotransferase-like protein (QPCTL) is a newly discovered enzyme that has sparked interest owing to its possible role in cancer genesis and progression. Initially discovered as a post-translational modification regulator of protein maturation, QPCTL has emerged as a key participant in cancer biology. Recent research has linked QPCTL to numerous essential cancer-related processes, including cell proliferation, migration, invasion, and apoptosis.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Department of Physiology, Pain Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China.
Hypertension is one of the major risk factors for morbidity and mortality worldwide. In this study, Mendelian randomization was utilized to investigate how dietary supplement intake can impact hypertension based on circulating plasma metabolite genome-wide association study (GWAS) datasets, protein quantitative trait loci (pQTLs) of plasma proteins, and multiple public summary-level GWAS data. Pathway enrichment analysis combined with the results of inverse variance weighted Mendelian randomization revealed that a lower risk of hypertension was associated with the dietary intake of glucosamine, an anti-inflammatory supplement: odds ratio (OR) (95% CI): 0.
View Article and Find Full Text PDFPLoS One
November 2024
Department of Clinical Laboratory, Gongli Hospital of Shanghai Pudong New Area, Shanghai, China.
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