Activation of human pancreatic juice

Rinderknecht, H.; Renner, Ian G.; Carmack, C

doi:10.1016/0009-8981(76)90185-6

Cited by 28 publications

(29 citation statements)

References 9 publications

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“…This substitution also affects the substrate selectivity of trypsin IV/mesotrypsin. Thus, in contrast to trypsin I and II, trypsin IV/mesotrypsin does not activate chymotrypsinogen or trypsinogen I and II (4,9,48). This substitution may also affect the capacity of trypsin IV to cleave and activate PARs.…”

Section: Discussionmentioning

confidence: 98%

“…Although the reason for this reduced potency of trypsin IV is unknown, the arginine to glycine substitution of trypsin IV is a probable explanation, because it affects the ability of trypsin IV/mesotrypsin to cleave other proteins (4,9,48). Trypsin IV also activated PAR 1 , but with reduced potency compared with trypsin I or thrombin (24).…”

Section: Discussionmentioning

confidence: 99%

“…Although PRSS3 evolved late in history, by inter-chromosomal duplication that occurred after the divergence of Old World monkeys and hominids, and was maintained as an active entity (8), the function of mesotrypsin/ trypsin IV are unknown. Mesotrypsinogen is only a minor component of pancreatic exocrine secretions (9). Trypsinogen IV is expressed by neurons and glial cells, mainly astrocytes, of human brain and spinal cord, as well as by epithelial cells of the human intestine, airway, and prostate, which also express enteropeptidase (3, 10 -12).…”

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confidence: 99%

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Trypsin IV or Mesotrypsin and p23 Cleave Protease-activated Receptors 1 and 2 to Induce Inflammation and Hyperalgesia

Knecht

Cottrell

Amadesi

et al. 2007

Journal of Biological Chemistry

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Although principally produced by the pancreas to degrade dietary proteins in the intestine, trypsins are also expressed in the nervous system and in epithelial tissues, where they have diverse actions that could be mediated by protease-activated receptors (PARs). We examined the biological actions of human trypsin IV (or mesotrypsin) and rat p23, inhibitor-resistant forms of trypsin. The zymogens trypsinogen IV and pro-p23 were expressed in Escherichia coli and purified to apparent homogeneity. Enteropeptidase cleaved both zymogens, liberating active trypsin IV and p23, which were resistant to soybean trypsin inhibitor and aprotinin. (trypsin IV and p23) mice. Trypsin IV and p23 caused thermal hyperalgesia and mechanical allodynia and hyperalgesia in mice, and these effects were absent in PAR 2 ؊/؊ mice but maintained in PAR 1 ؊/؊ mice. Thus, trypsin IV and p23 are inhibitor-resistant trypsins that can cleave and activate PARs, causing PAR 1 -and PAR 2 -dependent inflammation and PAR 2 -dependent hyperalgesia.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Trypsin IV or Mesotrypsin and p23 Cleave Protease-activated Receptors 1 and 2 to Induce Inflammation and Hyperalgesia

Knecht

Cottrell

Amadesi

et al. 2007

Journal of Biological Chemistry

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“…In humans, trypsinogen is secreted in three isoforms, cationic trypsinogen, anionic trypsinogen, and mesotrypsinogen. Cationic trypsinogen (Ϸ50-70%) and anionic trypsinogen (Ϸ30-40%) make up the bulk of trypsinogens in the pancreatic juice, whereas mesotrypsinogen accounts for 2-10% (1)(2)(3)(4)(5). Physiological activation of trypsinogen to trypsin in the duodenum is catalyzed by enteropeptidase (enterokinase), a highly specialized serine protease in the brushborder membrane of enterocytes.…”

mentioning

confidence: 99%

“…6 and references therein). Inactivation of intrapancreatic trypsin through trypsin-mediated trypsin degradation (autolysis) or by an unidentified serine protease (enzyme Y) was therefore proposed to be protective against pancreatitis (7)(8)(9)(10)(11). This notion received support from the discovery that the R122H mutation, which eliminates the Arg 122 autolytic site in cationic trypsinogen, causes autosomal dominant hereditary pancreatitis in humans (9).…”

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confidence: 99%

Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht's enzyme Y

Szmola

Sahin–Tóth

2007

Proc. Natl. Acad. Sci. U.S.A.

147

141

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Digestive trypsins undergo proteolytic breakdown during their transit in the human alimentary tract, which has been assumed to occur through trypsin-mediated cleavages, termed autolysis. Autolysis was also postulated to play a protective role against pancreatitis by eliminating prematurely activated intrapancreatic trypsin. However, autolysis of human cationic trypsin is very slow in vitro, which is inconsistent with the documented intestinal trypsin degradation or a putative protective role. Here we report that degradation of human cationic trypsin is triggered by chymotrypsin C, which selectively cleaves the Leu 81 -Glu 82 peptide bond within the Ca 2؉ binding loop. Further degradation and inactivation of cationic trypsin is then achieved through tryptic cleavage of the Arg 122 -Val 123 peptide bond. Consequently, mutation of either Leu 81 or Arg 122 blocks chymotrypsin C-mediated trypsin degradation. Calcium affords protection against chymotrypsin C-mediated cleavage, with complete stabilization observed at 1 mM concentration. Chymotrypsin C is highly specific in promoting trypsin degradation, because chymotrypsin B1, chymotrypsin B2, elastase 2A, elastase 3A, or elastase 3B are ineffective. Chymotrypsin C also rapidly degrades all three human trypsinogen isoforms and appears identical to enzyme Y, the enigmatic trypsinogen-degrading activity described by Heinrich Rinderknecht in 1988. Taken together with previous observations, the results identify chymotrypsin C as a key regulator of activation and degradation of cationic trypsin. Thus, in the high Ca 2؉ environment of the duodenum, chymotrypsin C facilitates trypsinogen activation, whereas in the lower intestines, chymotrypsin C promotes trypsin degradation as a function of decreasing luminal Ca 2؉ concentrations. chronic pancreatitis ͉ digestive enzymes ͉ trypsinogen degradation

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Enteropeptidase levels in duodenal juice of normal subjects and patients with gastrointestinal disease

1978

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Enteropeptidase, trypsin, and chymotrypsin activity in basal and secretin-stimulated duodenal juice of 20 normal adult volunteers and 15 patients with gastrotestinal disease were determined. All enzyme concentrations showed skew distributions, but fluctuations in the secretin-stimulated juices were less pronouced than in the basal secretions. Secretin administration had no influence on the release of enteropeptidase from human duodenal mucosa, but resulted in a very small increase in secretion of pancreatic enzymes. Six out of seven patients with chronic alcoholic pancreatitis or cancer of the pancreas exhibited highly significant elevations of enteropeptidase in their basal as well as secretin-stimulated duodenal juice. It is suggested that raised luminal enteropeptidase activity may be the result of pancreatic insufficiency or elevated blood glucagon concentrations.

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Activation of human pancreatic juice

Cited by 28 publications

References 9 publications

Trypsin IV or Mesotrypsin and p23 Cleave Protease-activated Receptors 1 and 2 to Induce Inflammation and Hyperalgesia

Trypsin IV or Mesotrypsin and p23 Cleave Protease-activated Receptors 1 and 2 to Induce Inflammation and Hyperalgesia

Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht's enzyme Y

Enteropeptidase levels in duodenal juice of normal subjects and patients with gastrointestinal disease

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