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Hereditary Pancreatitis
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Following the localization of several chromosomal markers on the long arm of chromosome 7, a genetic defect involving an arginine to histidine substitution in codon 122 (R122H) was identified in the cationic trypsinogen serine protease 1 (PRSS1) gene on chromosome 7q34 by Whitcomb and coworkers in 1996. Detection of further PRSS1 mutations (e.g., A16 V, D22G, K23R, N29I, N29 T, R122C) lent support for the role of this trypsin-encoding gene in the pathogenesis of hereditary pancreatitis, and provided impetus for the search of additional genes involved in hereditary pancreatitis, including the SPINK1 (serine protease inhibitor Kazal type 1) on chromosome 5q32 in 2009, the CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7q31.2 in 2010, and the CTRC (chymotrypsin C) gene on chromosome 1p36.21 in 2012 [1,4,5].
Proteomic analysis of pancreatic ductal adenocarcinoma
Published in Expert Review of Proteomics, 2020
Paula Meleady, Rozana Abdul Rahman, Michael Henry, Michael Moriarty, Martin Clynes
There have been a number of recent studies investigating the proteome of PDAC tissue to identify new markers of PDAC and a summary of such studies is outlined in Table 2. A label-free LC-MS/MS analysis on three pairs of PDAC tumor and adjacent tissues resulted in the identification of 40 proteins with at least a 3-fold expression difference between the patient groups, including four proteins from the carboxypeptidase family: carboxypeptidase A1 (CPA1), A2 (CPA2), B1 (CPB1), and chymotrypsin C (CTRC) [24]. Follow-on immunohistochemistry of a tissue microarray from 90 PDAC patients demonstrated that CPB1 was downregulated over 7-fold (n = 81) in tumor tissue compared with the peritumor tissue, and analysis of 208 pancreatic tissues from PDAC tumor, peritumor, and pancreatitis confirmed downregulation of CPB1 in the PDAC patients [24]. In another proteomic study, cofilin-1 (CFL1) was identified as upregulated in PDAC tissue and was confirmed by immunohistochemistry [80].
Discovery of differentially expressed genes in the intestines of Pelteobagrus vachellii within a light/dark cycle
Published in Chronobiology International, 2020
Chuanjie Qin, Jiaxian Sun, Jun Wang, Yongwang Han, He Yang, Qingchao Shi, Yunyun Lv, Peng Hu
Similar to mammals, the digestion and absorption of proteins in fish includes the hydrolysis of proteins and amino acid transport. In rats, Völkl and Poort (1983) indicated the existence of a clear-cut circadian rhythm in protein synthesis. Alkaline protease activity in the midgut of Nile tilapia (Oreochromis niloticus) showed a daily rhythm whose achrophase occurred at the beginning of the dark phase (Guerra-Santos et al. 2016). The present study showed that 34 DEGs were found within a light/dark cycle, which include genes encoding digestive enzymes, aminopeptidases, and amino acid transporters. The mRNA expression in ZT0 was higher than that at ZT6, ZT12, and ZT18, for genes encoding chymotrypsinogen 2, trypsin-3, chymotrypsin-C, puromycin-sensitive aminopeptidase, and glutamyl aminopeptidase. These enzymes are involved of the cleavage of lysine, arginine, tyrosine, tryptophan, phenylalanine, glutamate, aspartate, and methionine (Gregory and Dagmar 2004; Polgár 2005). The upregulated expression of these digestive enzymes in ZT0 might suggest that the maximum proteolysis of these amino acids occurs at night. Similarly, pancreatic protease activities (trypsinogen and chymotrypsinogen) in chicken showed a 24-hour cyclic rhythm (Rideau et al. 1983). The highest tryptic activities were found at 19:00, and the activities were lowest from 01:00 to 07:00 (Fujii et al. 2007). However, the expression of pepsin A mRNA was upregulated during the day. This enzyme efficiently in cleaves peptide bonds between hydrophobic amino acids, phenylalanine, tryptophan, and tyrosine. Similarly, a significant circadian rhythm was observed for pepsin efflux in the rat, with an acrophase value at 06:49 h after lights on, which continued during the lights-on resting phase (Barattini et al. 1993).
Trypsinogen and chymotrypsinogen: potent anti-tumor agents
Published in Expert Opinion on Biological Therapy, 2021
Aitor González-Titos, Pablo Hernández-Camarero, Shivan Barungi, Juan Antonio Marchal, Julian Kenyon, Macarena Perán
Additionally, the human pancreas secretes different isoforms of Trypsinogen and Chymotrypsinogen. Three different isoforms of Trypsinogen: cationic isoform, anionic isoform and Mesotrypsinogen have been described. The prevalent form is the cationic isoform followed by the anionic isoform and finally the Mesotrypsinogen that represents less than 5% [7,23]. Cationic and anionic Trypsinogen have similar characteristics with respect to their molecular weight, amino acid composition, and optimal pH [24]. The differences between anionic and cationic isoforms involve the ability of cationic isoforms to autoactivate at an acidic pH and the higher stability of cationic Trypsinogen. On the other hand, the anionic isoform autolyzes itself faster at neutral or alkaline pH [25]. In addition, calcium ions are unable to stabilize the anionic isoform against autolysis [24]. The enzyme Mesotrypsin is characterized by its resistance to trypsin inhibitors and for promoting their degradation [26]. Specifically, it has been reported that this resistance is due to the presence of an arginine instead of glycine at position 198 [27]. Regarding Chymotrypsinogen, four different isoforms have been described: Chymotrypsinogen/Chymotrypsin B1, Chymotrypsinogen/Chymotrypsin B2, Chymotrypsinogen/Chymotrypsin C and Chymotrypsin-like protease. Chymotrypsin B1 has a preference for amino acids like Tryptophan and Tyrosine, while Chymotrypsin B2 has a preference for amino acids such as Phenylalanine and Tyrosine [28]. Chymotrypsin C preferentially cleaves the peptide bonds located in the C terminal of tyrosine, methionine and leucine and it can activate Trypsinogen by cleaving at the activation peptide between Phe-18 and Asp-19 residues [15]. Conversely, it can also cause the degradation of Trypsin by cutting into the calcium-bindingloop between the Leu-81 and Glu-82 residues which bind to Ca2+ to stabilize the protein resulting in a rapid degradation and inactivation of cationic trypsinogen. This may be a regulatory mechanism when trypsinogen is overexpressed or activated too early [29]. The specific cleavage of the Leu81-Glu82 peptide bond in human cationic trypsinogen by CTRC is primarily determined by its distinctively high activity on leucyl peptide bonds, with the P1ʹ Glu82, P3ʹ Asn84 and P4ʹ Glu85 residues serving as additional specificity determinants [28]