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Intracellular Peptide Turnover: Properties and Physiological Significance of the Major Peptide Hydrolases of Brain Cytosol
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
One of the most interesting and unique features of the soluble metalloendopeptidase is its substrate specificity. The substrate specificity of most proteinases can be readily described e.g. prolyl oligopeptidase (cleavage at the carboxyl side of a proline residue), neprilysin (cleavage at the amino side of a hydrophobic amino acid), trypsin (cleavage at the carboxyl side of a basic amino acid), etc. Although soluble metalloendopeptidase-catalyzed cleavages commonly occur at the carboxyl side of a hydrophobic amino acid, neurotensin is degraded by cleavage between two arginyl residues, a His-Trp bond is one of the cleavage sites in LHRH and a Pro-Gin bond in substance P is hydrolyzed. When a series of synthetic substrates was studied, a preference for aromatic amino acid residues in the P1 and P2 positions was seen. In addition there was a marked beneficial effect when an aromatic amino acid was present in the P3’ position. The latter substituent decreased the Km and increased the kcat. It could account in part for the unusual specificity.
Novel approaches to anti-obesity drug discovery with gut hormones over the past 10 years
Published in Expert Opinion on Drug Discovery, 2019
Frances Rose, Stephen Bloom, Tricia Tan
The circulating half life of PYY3–36 is only 15 minutes [31], which limits pharmacological utility. Furthermore, the supraphysiological doses required for periodic administration of PYY to reduce food intake and induce weight loss are associated with unacceptable levels of nausea [32]. Metalloendopeptidases have been implicated in the degradation of PYY, with co-administration of actinoin, a metalloendopeptidase inhibitor, prolonging its anorectic effect [33]. This suggests that specific inhibitors or analogues of PYY that are resistant to cleavage may be useful as anti-obesity therapeutics. An alternative strategy is to use reversible polyethylene glycol (PEG)ylation, coupling PYY3–36 to a 40 kDa PEG group via a spontaneously cleavable linker, which is gradually hydrolyzed, slowly releasing unmodified PYY3–36 into the circulation [34]. Long-acting analogues of PYY are currently being tested in Phase I trials (e.g. Novo Nordisk NN-9747, Imperial College Y14 – Clinicaltrials.org NCT03673111), to establish their safety in human volunteers and to gather preliminary efficacy data.
Responses to iron oxide and zinc oxide nanoparticles in echinoderm embryos and microalgae: uptake, growth, morphology, and transcriptomic analysis
Published in Nanotoxicology, 2020
Anne-Marie Genevière, Evelyne Derelle, Marie-Line Escande, Nigel Grimsley, Christophe Klopp, Christine Ménager, Aude Michel, Hervé Moreau
Among the 196 DE contigs highly up-regulated (LFC > 3) after ZnO ENP exposure, 23 encoded proteins of the metallothionein (MT) family (w/o an assigned GO term), all of them being more severely induced upon ZnSO4 exposure (Figure S3). Seven were also up-regulated, though more weakly, in the presence of FeCl3 while none of them were stimulated by Fe2O3 ENPs. A notable effect was also observed for three contigs encoding metalloendopeptidases, MMP16 precursor, BP10 and a type IV collagenase, which are highly induced in response to zinc, either as ENP or ionic. Nine other Zn-dependent contigs encoding metalloendopeptidases were also induced, less severely, in response to both forms of zinc metal.
Investigating material basis and molecular mechanism of Qing Cuo formula in the treatment of acne based on animal experiments, UPLC-LTQ-Orbitrap-MS and network pharmacology
Published in Pharmaceutical Biology, 2023
Yanqi Cao, Jinfeng Liang, Chunguo Wang, Xuejie Bao, Siqi Li, Qi Liu, Bin Zeng, David Humberto Lopez, Ruoxi Yu
The results of GO analysis showed that there were 141 terms, including 103 terms for biological process (BP), 14 terms for cellular component (CC) and 24 terms for molecular function (MF). The results of each term were sorted by significance, and the top 10 findings of each analysis were selected for display (Figure 7). Analyses using the GO database showed that the main enrichment of genes in the BP category was ‘response to beta-amyloid’, ‘collagen catabolic process’, ‘extracellular matrix disassembly’, ‘extracellular matrix organization’ and ‘response to hypoxia’. The main MF categories were ‘endopeptidase activity’, ‘serine-type endopeptidase activity’, ‘metallopeptidase activity’ and ‘metalloendopeptidase activity’. The main CC categories were ‘extracellular space’ and ‘extracellular region’. It can be discovered that these functional terms are highly relevant to extracellular matrix metabolism. KEGG metabolic pathway enrichment analysis obtained 48 enrichment results and information on the top 10 entries were shown in Figure 8. According to the classifications and descriptions provided by KEGG, these terms can be roughly classified into metabolism, environmental information processing, cellular processes, organismal systems and human diseases (Figure 9). Among them, organismal systems mainly involve the pathways related to the immune system, such as C-type lectin receptor signalling pathway, IL-17 signalling pathway and T cell receptor signalling pathway, and the pathways related to the endocrine system, such as endocrine system, ovarian steroidogenesis, relaxin signalling pathway, oestrogen signalling pathway and GnRH signalling pathway.