Effects of chronic alcohol abuse on exocrine pancreatic secretion in man

Rinderknecht, H.; Stace, Nigel H.; Renner, Ian G.

doi:10.1007/bf01318373

Cited by 79 publications

(50 citation statements)

References 22 publications

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“…On the basis of their relative isoelectric points and electrophoretic mobility, these are commonly referred to as cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), and mesotrypsinogen (PRSS3). Normally, cationic trypsinogen represents approximately twothirds of total trypsinogen in the pancreatic juice, while anionic trypsinogen makes up approximately one-third [Guy et al, 1978;Rinderknecht et al, 1979Rinderknecht et al, , 1985. Mesotrypsinogen is a minor species, accounting for 2 to 10% of human trypsinogens [Rinderknecht et al, 1984].…”

Section: Introductionmentioning

confidence: 99%

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

et al. 2006

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Section: Introductionmentioning

confidence: 99%

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

et al. 2006

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“…The isoenzymes are encoded by separate genes, the PRSS1 (protease, serine, 1), PRSS2 and PRSS3 genes (for a recent review see [1] and references therein). Cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2) make up the bulk of secreted trypsinogens in the pancreatic juice, while mesotrypsinogen (PRSS3) accounts for 2-10 % [2][3][4][5][6]. Typically, there is approximately twice as much cationic trypsinogen as anionic trypsinogen, but this ratio is reversed in chronic alcoholism or chronic pancreatitis [3,5].…”

Section: Human Trypsinogens and Pancreatitis-associated Trypsinogen Mmentioning

confidence: 99%

“…Cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2) make up the bulk of secreted trypsinogens in the pancreatic juice, while mesotrypsinogen (PRSS3) accounts for 2-10 % [2-6]. Typically, there is approximately twice as much cationic trypsinogen as anionic trypsinogen, but this ratio is reversed in chronic alcoholism or chronic pancreatitis [3,5]. The significance of the "isoform reversal" is unknown [7].…”

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confidence: 99%

Biochemical Models of Hereditary Pancreatitis

Sahin–Tóth

2006

Endocrinology and Metabolism Clinics of North America

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The past decade has witnessed remarkable progress in the genetics of chronic pancreatitis. Mutations of the PRSS1 gene encoding cationic trypsinogen and the SPINK1 gene encoding pancreatic secretory trypsin inhibitor were found in association with hereditary, familial or sporadic chronic pancreatitis; and the genotype -phenotype correlations have been characterized at the clinical level. Despite these accomplishments, our understanding of the molecular mechanism(s) through which PRSS1 and SPINK1 mutations cause chronic pancreatitis has remained sketchy. Pancreatitis-associated gene mutations are believed to result in uncontrolled trypsin activity in the pancreas. Thus, PRSS1 mutations would cause a gain of (trypsin) function, while SPINK1 mutations would result in the loss of a (trypsin inhibitor) function. However, experimental identification of the disease-relevant functional alterations caused by PRSS1 or SPINK1 mutations proved to be challenging, as results of biochemical analyses lent themselves to different interpretations. The present review focuses on PRSS1 mutations and summarizes the salient biochemical findings in the context of the mechanistic models that attempt to explain the connection between mutations and hereditary pancreatitis. Human Trypsinogens and Pancreatitis-Associated Trypsinogen MutationsThe human pancreas produces the digestive pro-enzyme trypsinogen in three isoforms. On the basis of their relative isoelectric points and electrophoretic mobility, these are commonly referred to as cationic trypsinogen, anionic trypsinogen, and mesotrypsinogen. The isoenzymes are encoded by separate genes, the PRSS1 (protease, serine, 1), PRSS2 and PRSS3 genes (for a recent review see [1] and references therein). Cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2) make up the bulk of secreted trypsinogens in the pancreatic juice, while mesotrypsinogen (PRSS3) accounts for 2-10 % [2-6]. Typically, there is approximately twice as much cationic trypsinogen as anionic trypsinogen, but this ratio is reversed in chronic alcoholism or chronic pancreatitis [3,5]. The significance of the "isoform reversal" is unknown [7]. Human trypsinogens are synthesized as pre-pro-enzymes with a signal peptide of 15 amino acids, followed by the 8 amino acid long pro-peptide, the trypsinogen activation peptide. The signal-peptide is removed upon entry into the endoplasmic reticulum lumen and the proenzymes are packaged into zymogen granules and eventually secreted into the pancreatic juice. Physiological activation of trypsinogen to trypsin takes place in the duodenum by enteropeptidase (enterokinase), a highly specialized serine protease in the brush-border membrane of enterocytes. Trypsin can also activate trypsinogen, a process termed autoactivation, which in the duodenum may have a physiological role in facilitating zymogen activation, whereas inappropriate autoactivation in the pancreas might cause pancreatitis. Mutations in the PRSS1 gene have been identified in patients with hereditary pancreatitis, fam...

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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%

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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Effects of chronic alcohol abuse on exocrine pancreatic secretion in man

Cited by 79 publications

References 22 publications

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Biochemical Models of Hereditary Pancreatitis

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

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