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Gastroenterology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Chronic pancreatitis is idiopathic or has autosomal dominant inheritance with variable penetrance (40–80%). Recognised genetic associations include cationic trypsinogen (PRSS1), SPINK 1, CFTR and chymotrypsinogen C (CTRC) mutations.
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Published in Anton Sebastian, A Dictionary of the History of Medicine, 2018
Trypsin Alimentary enzyme discovered by Aleksander Danilevsky (1838–1923) in 1862 and isolated by a German biochemist, Wilhelm Friedrich Kühne (1837–1900).Kühne also coined the term enzyme in 1878 to denote organic substances which activated chemical reactions A crystalline form was obtained by American biochemist, John Howard Northrop (1891–1987) of NewYork in 1932. Chymotrypsinogen was isolated by Northrop in 1935, who wrote Crystalline Enzymes in 1939.
The accessory organs: Pancreas, liver and gallbladder
Published in Paul Ong, Rachel Skittrall, Gastrointestinal Nursing, 2017
A number of proteases are produced by acini cells in the pancreas. Two important ones are trypsin and chymotrypsin. As with pepsin in the stomach, these enzymes are manufactured in the inactive forms of trypsinogen and chymotrypsinogen to prevent autodigestion of pancreatic tissue. Trypsinogen is converted to the active trypsin by the enzyme enterokinase which is secreted by intestinal enterocyte epithelial cells. Once formed trypsin also has the effect of activating trypsinogen and chymotrypsinogen. Both trypsin and chymotrypsin destroy the peptide bonds linking amino acids together. This serves to break down polypeptides to peptides, therefore making peptide chains shorter, but these proteases cannot break down the peptides to the single molecule amino acids. This role is largely performed by peptidases. This is an enzyme released from the brush border membrane of the intestinal enterocyte epithelial cells.
Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed
Published in Hematology, 2018
Antonio Girolami, Silvia Ferrari, Elisabetta Cosi, Bruno Girolami, Anna Maria Lombardi
Our knowledge about the dysforms have changed during the last few years. Actually the first data about the existence of a severe procoagulant state associated with a mild bleeding tendency dated back to 2002 [11]. In that year Akhavan et al. reported an 11 years old girl from Iran who had only a mild-to-moderate bleeding tendency despite having prothrombin level of less than 1% but an antigen level of 61%. On the suspicion of a dysfunctional protein further studies showed that the underlying mutation was Arg67His substitution (chymotrypsinogen numbering that is equivalent to the Arg382His mutation). Furthermore, it was demonstrated a decreased activation of protein C, a decreased binding to thrombomodulin, a severe impairment of thrombin inhibition by heparin cofactor II and, finally, a decrease of prothrombin activation by the FXa–FVa complex. The complex defect caused by the Arg67His mutation was cautiously concluded to affect both the coagulant and the anticoagulant activities of thrombin. It was thought that there was a balance between these two opposing forces [11]. This interesting observation remained silent for several years and the prothrombin defects were always considered to be responsible of a bleeding tendency. Several dysprothrombinemias were reported but no thrombosis event was ever mentioned [2,3,12–17].
Clinical and genetic predictors of diabetes drug’s response
Published in Drug Metabolism Reviews, 2019
Adriana Fodor, Angela Cozma, Ramona Suharoschi, Adela Sitar-Taut, Gabriela Roman
A variant of CTRB1/2 (rs7202877 T→G) gene, encoding chymotrypsinogen 1 and 2, has been previously shown to be protective against diabetes development. Carriers of the minor G allele (10% of the patients) showed a 0.5% smaller reduction in HbA1c after gliptin therapy (84% with sitagliptin) compared with TT-allele patients ('t Hart et al. 2013).
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]