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International Journal of Molecular... May 2021Genomic and phylogenetic analyses of various invertebrate phyla revealed the existence of genes that are evolutionarily related to the vertebrate's decapeptide... (Review)
Review
Genomic and phylogenetic analyses of various invertebrate phyla revealed the existence of genes that are evolutionarily related to the vertebrate's decapeptide gonadotropin-releasing hormone (GnRH) and the GnRH receptor genes. Upon the characterization of these gene products, encoding peptides and putative receptors, GnRH-related peptides and their G-protein coupled receptors have been identified. These include the adipokinetic hormone (AKH) and corazonin (CRZ) in insects and their cognate receptors that pair to form bioactive signaling systems, which network with additional neurotransmitters/hormones (e.g., octopamine and ecdysone). Multiple studies in the past 30 years have identified many aspects of the biology of these peptides that are similar in size to GnRH and function as neurohormones. This review briefly describes the main activities of these two neurohormones and their receptors in the fruit fly . The similarities and differences between AKH/CRZ and mammalian GnRH signaling systems are discussed. Of note, while GnRH has a key role in reproduction, AKH and CRZ show pleiotropic activities in the adult fly, primarily in metabolism and stress responses. From a protein evolution standpoint, the GnRH/AKH/CRZ family nicely demonstrates the developmental process of neuropeptide signaling systems emerging from a putative common ancestor and leading to divergent activities in distal phyla.
Topics: Amino Acid Sequence; Animals; Drosophila melanogaster; Evolution, Molecular; Gonadotropin-Releasing Hormone; Humans; Insect Hormones; Insect Proteins; Neuropeptides; Neurotransmitter Agents; Oligopeptides; Phylogeny; Pyrrolidonecarboxylic Acid; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34068603
DOI: 10.3390/ijms22095035 -
Mass Spectrometry Reviews Jan 2018It is now 25 years since we commenced the study of the negative-ion fragmentations of peptides and we have recently concluded this research with investigations of the... (Review)
Review
It is now 25 years since we commenced the study of the negative-ion fragmentations of peptides and we have recently concluded this research with investigations of the negative-ion chemistry of most post-translational functional groups. Our first negative-ion peptide review (Bowie, Brinkworth, & Dua, 2002) dealt with the characteristic backbone fragmentations and side-chain cleavages from (M-H) ions of underivatized peptides, while the second (Bilusich & Bowie, 2009) included negative-ion backbone cleavages for Ser and Cys and some initial data on some post-translational groups including disulfides. This third and final review provides a brief summary of the major backbone and side chain cleavages outlined before (Bowie, Brinkworth, & Dua, 2002) and describes the quantum mechanical hydrogen tunneling associated with some proton transfers in enolate anion/enolate systems. The review then describes, in more depth, the negative-ion cleavages of the post-translational groups Kyn, isoAsp, pyroglu, disulfides, phosphates, and sulfates. Particular emphasis is devoted to disulfides (both intra- and intermolecular) and phosphates because of the extensive and spectacular anion chemistry shown by these groups. © 2016 Wiley Periodicals, Inc. Mass Spec Rev.
Topics: Amino Acid Sequence; Animals; Anions; Disulfides; Humans; Isoaspartic Acid; Kynurenine; Peptides; Phosphates; Protein Processing, Post-Translational; Pyrrolidonecarboxylic Acid; Spectrometry, Mass, Electrospray Ionization; Sulfates
PubMed: 27018865
DOI: 10.1002/mas.21501 -
Molecular Neurodegeneration Jun 2016Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation... (Review)
Review
Immunization against amyloid-β (Aβ) peptides deposited in Alzheimer's disease (AD) has shown considerable therapeutic effect in animal models however, the translation into human Alzheimer's patients is challenging. In recent years, a number of promising Aβ immunotherapy trials failed to reach primary study endpoints. Aside from uncertainties in the selection of patients and the start and duration of treatment, these results also suggest that the mechanisms underlying AD are still not fully understood. Thorough characterizations of protein aggregates in AD brain have revealed a conspicuous heterogeneity of Aβ peptides enabling the study of the toxic potential of each of the major forms. One such form, amino-terminally truncated and modified pyroglutamate (pGlu)-3 Aβ peptide appears to play a seminal role for disease initiation, qualifying it as novel target for immunotherapy approaches.
Topics: Alzheimer Disease; Alzheimer Vaccines; Amyloid beta-Protein Precursor; Animals; Humans; Pyrrolidonecarboxylic Acid
PubMed: 27363697
DOI: 10.1186/s13024-016-0115-2 -
Journal of Assisted Reproduction and... Dec 2022Polycystic ovary syndrome is a complex heterogeneous endocrine disorder associated with established metabolic abnormalities and is a common cause of infertility in...
PURPOSE
Polycystic ovary syndrome is a complex heterogeneous endocrine disorder associated with established metabolic abnormalities and is a common cause of infertility in females. Glutathione metabolism in the cumulus cells (CCs) of women with PCOS may be correlated to the quality of oocytes for infertility treatment; therefore, we used a metabolomics approach to examine changes in CCs from women with PCOS and oocyte quality.
METHODS
Among 135 women undergoing fertility treatment in the present study, there were 43 women with PCOS and 92 without. CCs were collected from the two groups and levels of pyroglutamic acid were measured using LC-MS/MS followed by qPCR and Western blot analysis to examine genes and proteins involved in pyroglutamic acid metabolism related to glutathione synthesis.
RESULTS
Women with PCOS showed increased levels of L-pyroglutamic acid, L-glutamate, and L-phenylalanine and decreased levels of Cys-Gly and N-acetyl-L-methionine. Gene expression of OPLAH, involved in pyroglutamic synthesis, was significantly increased in women with PCOS compared with those without. Gene expression of GSS was significantly decreased in women with PCOS and synthesis of glutathione synthetase protein was decreased. Expression of nuclear factor erythroid 2-related factor 2, involved in resistance to oxidative stress, was significantly increased in women with PCOS.
CONCLUSIONS
CCs of women with PCOS showed high concentrations of pyroglutamic acid and reduced glutathione synthesis, which causes oxidative stress in CCs, suggesting that decreased glutathione synthesis due to high levels of pyroglutamic acid in CCs may be related to the quality of oocytes in women with PCOS.
Topics: Humans; Female; Polycystic Ovary Syndrome; Cumulus Cells; Pyrrolidonecarboxylic Acid; Chromatography, Liquid; Tandem Mass Spectrometry; Oocytes; Infertility; Glutathione
PubMed: 36322230
DOI: 10.1007/s10815-022-02647-1 -
Journal of Medicinal Chemistry May 2021Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans... (Review)
Review
Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.
Topics: Aminoacyltransferases; Amyloid beta-Peptides; Biological Products; Enzyme Inhibitors; Humans; Imidazoles; Inflammation; Neurodegenerative Diseases; Pyrrolidonecarboxylic Acid; Up-Regulation
PubMed: 34000808
DOI: 10.1021/acs.jmedchem.1c00325 -
The Biochemical Journal Sep 2020Heart failure results from the heart's inability to carryout ventricular contraction and relaxation, and has now become a worldwide problem. During the onset of heart... (Review)
Review
Heart failure results from the heart's inability to carryout ventricular contraction and relaxation, and has now become a worldwide problem. During the onset of heart failure, several signatures are observed in cardiomyocytes that includes fetal reprogramming of gene expression where adult genes are repressed and fetal genes turned on, endoplasmic reticulum stress and oxidative stress. In this short review and analysis, we examine these different phenomenon from the viewpoint of the glutathione cycle and the role of the recently discovered Chac1 enzyme. Chac1, which belongs to the family of γ-glutamylcyclotransferases, is a recently discovered member of the glutathione cycle, being involved in the cytosolic degradation of glutathione. This enzyme is induced during the Endoplasmic Stress response, but also in the developing heart. Owing to its exclusive action on reduced glutathione, its induction leads to an increase in the oxidative redox potential of the cell that also serves as signaling mechanism for calcium ions channel activation. The end product of Chac1 action is 5-oxoproline, and studies with 5-oxoprolinase (OPLAH), an enzyme of the glutathione cycle has revealed that down-regulation of OPLAH can lead to the accumulation of 5-oxproline which is an important factor in heart failure. With these recent findings, we have re-examined the roles and regulation of the enzymes in the glutathione cycle which are central to these responses. We present an integrated view of the glutathione cycle in the cellular response to heart failure.
Topics: Animals; Endoplasmic Reticulum Stress; Glutathione; Heart Failure; Humans; Oxidative Stress; Pyroglutamate Hydrolase; Pyrrolidonecarboxylic Acid; gamma-Glutamylcyclotransferase
PubMed: 32886767
DOI: 10.1042/BCJ20200429 -
Frontiers in Immunology 2022Noninvasive methods for the early identify diagnosis of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) are current clinical challenges.
BACKGROUND
Noninvasive methods for the early identify diagnosis of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) are current clinical challenges.
METHODS
The serum metabolites of 20 healthy individuals and patients with prostatitis, BPH, or PCa were identified using untargeted liquid chromatography-mass spectrometry (LC-MS). In addition, targeted LC-MS was used to verify the organic acid metabolites in the serum of a validation cohort.
RESULTS
Organic acid metabolites had good sensitivity and specificity in differentiating prostatitis, BPH, and PCa. Three diagnostic models identified patients with PROSTATITIS: phenyllactic acid (area under the curve [AUC]=0.773), pyroglutamic acid (AUC=0.725), and pantothenic acid (AUC=0.721). Three diagnostic models identified BPH: citric acid (AUC=0.859), malic acid (AUC=0.820), and D-glucuronic acid (AUC=0.810). Four diagnostic models identified PCa: 3-hydroxy-3-methylglutaric acid (AUC=0.804), citric acid (AUC=0.918), malic acid (AUC=0.862), and phenyllactic acid (AUC=0.713). Two diagnostic models distinguished BPH from PCa: phenyllactic acid (AUC=0.769) and pyroglutamic acid (AUC=0.761). Three diagnostic models distinguished benign BPH from PROSTATITIS: citric acid (AUC=0.842), ethylmalonic acid (AUC=0.814), and hippuric acid (AUC=0.733). Six diagnostic models distinguished BPH from prostatitis: citric acid (AUC=0.926), pyroglutamic acid (AUC=0.864), phenyllactic acid (AUC=0.850), ethylmalonic acid (AUC=0.843), 3-hydroxy-3-methylglutaric acid (AUC=0.817), and hippuric acid (AUC=0.791). Three diagnostic models distinguished PCa patients with PROSTATITISA < 4.0 ng/mL from those with PSA > 4.0 ng/mL: 5-hydromethyl-2-furoic acid (AUC=0.749), ethylmalonic acid (AUC=0.750), and pyroglutamic acid (AUC=0.929). Conclusions: These results suggest that serum organic acid metabolites can be used as biomarkers to differentiate prostatitis, BPH, and PCa.
Topics: Male; Humans; Prostatic Hyperplasia; Prostatitis; Prostate-Specific Antigen; Meglutol; Pyrrolidonecarboxylic Acid; Prostatic Neoplasms; Biomarkers
PubMed: 36685547
DOI: 10.3389/fimmu.2022.998447 -
Acta Crystallographica. Section C,... Feb 2022Thermal-induced transformation of glutamic acid to pyroglutamic acid is well known. However, confusion remains over the exact temperature at which this happens....
Thermal-induced transformation of glutamic acid to pyroglutamic acid is well known. However, confusion remains over the exact temperature at which this happens. Moreover, no diffraction data are available to support the transition. In this article, we make a systematic investigation involving thermal analysis, hot-stage microscopy and single-crystal X-ray diffraction to study a one-pot thermal transition of glutamic acid to pyroglutamic acid and subsequent self-cocrystallization between the product (hydrated pyroglutamic acid) and the unreacted precursor (glutamic acid). The melt upon cooling gave a robust cocrystal, namely, glutamic acid-pyroglutamic acid-water (1/1/1), CHNO·CHNO·HO, whose structure has been elucidated from single-crystal X-ray diffraction data collected at room temperature. A three-dimensional network of strong hydrogen bonds has been found. A Hirshfeld surface analysis was carried out to make a quantitative estimation of the intermolecular interactions. In order to gain insight into the strength and stability of the cocrystal, the transferability principle was utilized to make a topological analysis and to study the electron-density-derived properties. The transferred model has been found to be superior to the classical independent atom model (IAM). The experimental results have been compared with results from a multipolar refinement carried out using theoretical structure factors generated from density functional theory (DFT) calculations. Very strong classical hydrogen bonds drive the cocrystallization and lend stability to the resulting cocrystal. Important conclusions have been drawn about this transition.
Topics: Crystallization; Crystallography, X-Ray; Glutamic Acid; Hydrogen Bonding; Pyrrolidonecarboxylic Acid
PubMed: 35119384
DOI: 10.1107/S2053229621013607 -
General and Comparative Endocrinology Dec 2014In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related... (Review)
Review
In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related peptide (ACP), and corazonin from arthropods. We conclude that these G protein-coupled receptors (GPCRs) are closely related and have a common evolutionary origin, which dates back to the split of Proto- and Deuterostomia, about 700 million years ago. We propose that in the protostomian lineage, the ancestral GnRH-like receptor gene duplicated as did its GnRH-like ligand gene, followed by diversification, leading to (i) a corazonin receptor gene and a corazonin-like ligand gene, and (ii) an AKH receptor gene and an AKH-like ligand gene in the Mollusca and Annelida. Subsequently, the AKH receptor and ligand genes duplicated once more, yielding the situation that we know from arthropods today, where three independent hormonal systems exist, signalling with AKH, ACP, and corazonin. Our model for the evolution of GnRH signaling in the Protostomia is a striking example of receptor-ligand co-evolution. This model has been developed using several bioinformatics tools (TBLASTN searches, phylogenetic tree analyses), which also helped us to annotate six novel AKH preprohormones and their corresponding AKH sequences from the following molluscs: the sea hare Aplysia californica (AKH sequence: pQIHFSPDWGTamide), the sea slug Tritonia diomedea (pQIHFSPGWEPamide), the fresh water snail Bithynia siamensis goniomphalos (pQIHFTPGWGSamide), the owl limpet Lottia gigantea (pQIHFSPTWGSamide), the oyster Crassostrea gigas (pQVSFSTNWGSamide), and the freshwater pearl mussel Hyriopsis cumingii (pQISFSTNWGSamide). We also found AKHs in the tardigrade Hysibius dujardini (pQLSFTGWGHamide), the rotifer Brachionus calycifloros (pQLTFSSDWSGamide), and the penis worm Priapulus caudatus (pQIFFSKGWRGamide). This is the first report, showing that AKH signaling is widespread in molluscs.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gonadotropin-Releasing Hormone; Insect Hormones; Insect Proteins; Invertebrates; Ligands; Male; Molecular Sequence Data; Multigene Family; Neuropeptides; Oligopeptides; Phylogeny; Pyrrolidonecarboxylic Acid; Receptors, G-Protein-Coupled; Receptors, LHRH; Receptors, Neuropeptide; Sequence Homology, Amino Acid
PubMed: 25058364
DOI: 10.1016/j.ygcen.2014.07.009 -
European Journal of Pharmacology Sep 2022Glutaminyl cyclases (QC) catalyze the cyclization of proteins and turn N-terminal glutamine or glutamic acid into N-terminal pyroglutamate, resulting in protection of... (Review)
Review
Glutaminyl cyclases (QC) catalyze the cyclization of proteins and turn N-terminal glutamine or glutamic acid into N-terminal pyroglutamate, resulting in protection of proteins from aminopeptidases and an increase of their stabilities. The aberrant N-terminal pyroglutamate has been found in various diseases, including Alzheimer's disease (AD), Huntington's disease (HD) and cancer. Two kinds of human QC, the secretory sQC and the Golgi resident gQC, are identified to date. Several substrates of sQC involving beta amyloid (Aβ), Huntington (HTT) protein and certain inflammatory mediators such as CCL2 and CX3CL1 have been observed to associate with neurodegenerative diseases and cancers. The Golgi resident gQC can modify N-terminus of CD47 that directly influences the interaction of CD47 and SIRPα resulting in the modulations of the immunological surveillance related mechanisms in cancer. Additionally, inflammatory chemokines CCL2 and CX3CL1 can also be modified by gQC. Several QC inhibitors with differential scaffold structures have been developed and investigated. Among these QC inhibitors, PQ912, a benzimidazole-based inhibitor, has been studied in a phase II clinical trial to treat AD. In this review, we will summarize the current knowledge about QCs' tissue expression patterns, their potential cellular substrates in the context of cancers, AD and HD. After introducing QCs' molecular structures and catalysis mechanisms, the structures and efficacies of the currently reported QCs' inhibitors will also be summarized.
Topics: Alzheimer Disease; Aminoacyltransferases; Amyloid beta-Peptides; CD47 Antigen; Humans; Neoplasms; Neurodegenerative Diseases; Pyrrolidonecarboxylic Acid
PubMed: 35948163
DOI: 10.1016/j.ejphar.2022.175178