Trypsinogen variants in pancreatic juice of healthy volunteers, chronic alcoholics, and patients with pancreatitis and cancer of the pancreas

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

doi:10.1136/gut.20.10.886

Cited by 81 publications

(50 citation statements)

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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%

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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Section: Human Trypsinogens and Pancreatitis-associated Trypsinogen Mmentioning

confidence: 99%

Biochemical Models of Hereditary Pancreatitis

Sahin–Tóth

2006

Endocrinology and Metabolism Clinics of North America

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“…Researchers have found that levels of mesotrypsinogen are increased in chronic alcoholics and decreased in patients with pancreatitis (3). These findings raise the question of whether inhibitor-resistant activity of mesotrypsin has a role in the pathogenesis of pancreatic diseases (4).…”

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Identification and Expression of the cDNA-encoding Human Mesotrypsin(ogen), an Isoform of Trypsin with Inhibitor Resistance

Nyaruhucha

Kito

Fukuoka

1997

Journal of Biological Chemistry

105

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The cDNA encoding a novel isoform of human trypsinogen was identified. The isoelectric points of the proenzyme and active forms calculated from the deduced amino acid sequence are consistent with those of mesotrypsin(ogen), known to be an inhibitor-resistant trypsin isoform. The cDNA attached with a bacterial signal peptide sequence was expressed in Escherichia coli. The recombinant proenzyme purified from periplasm showed enterokinase-dependent activation similar to a major isoform of human trypsinogen. The enzyme was far less inhibited by trypsin inhibitors such as soybean trypsin inhibitor, aprotinin, or pancreatic secretory trypsin inhibitor than the control trypsin. A gel filtration assay showed that the enzyme and aprotinin did not form a stable complex. It is noteworthy that the amino acid at position 198, which is in close vicinity to the active Ser, is Arg while those of other major trypsins are all Gly. It is concluded that the cloned cDNA encodes human mesotrypsinogen, a unique isoform of trypsinogen with inhibitor resistance.Pancreatic trypsin is a key enzyme, which leads to activation of a number of pancreatic digestive proenzymes including chymotrypsinogens, procarboxypeptidases, proelastases, and prophospholipase A 2 as well as trypsinogens themselves. Three different trypsinogens, which show unique isoelectric points (pI), have been described in human pancreatic juice using twodimensional isoelectric focusing/SDS-PAGE.

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“…The human pancreas secretes three isoforms as follows: cationic trypsinogen, anionic trypsinogen, and mesotrypsinogen, which are encoded by the PRSS1, PRSS2, and PRSS3 genes, respectively (1). Cationic and anionic trypsinogen constitute more than 95% of total trypsinogen in the pancreatic juice, with a slight preponderance of the cationic isoform (2)(3)(4). Interestingly, expression of anionic trypsinogen is increased in inflammatory and malignant diseases of the pancreas and in chronic alcoholism resulting in a reversal of the relative isoform amounts (4 -6).…”

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confidence: 99%

Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

Jancsó

Sahin–Tóth

2016

Journal of Biological Chemistry

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The human pancreas expresses two major trypsinogen isoforms, cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2). Mutations in PRSS1 cause hereditary pancreatitis by altering cleavage of regulatory nick sites by chymotrypsin C (CTRC) resulting in reduced trypsinogen degradation and increased autoactivation. Despite 90% identity with PRSS1 and a strong propensity for autoactivation, mutations in PRSS2 are not found in hereditary pancreatitis suggesting that activation of this isoform is more tightly regulated. Here, we demonstrated that CTRC promoted degradation and thereby markedly suppressed autoactivation of human anionic trypsinogen more effectively than previously observed with cationic trypsinogen. Increased sensitivity of anionic trypsinogen to CTRC-mediated degradation was due to an additional cleavage site at Leu-148 in the autolysis loop and the lack of the conserved Cys-139 -Cys-206 disulfide bond. Significant stabilization of anionic trypsinogen against degradation was achieved by simultaneous mutations of CTRC cleavage sites Leu-81 and Leu-148, autolytic cleavage site Arg-122, and restoration of the missing disulfide bridge. This stands in stark contrast to cationic trypsinogen where single mutations of either Leu-81 or Arg-122 resulted in almost complete resistance to CTRC-mediated degradation. Finally, processing of the trypsinogen activation peptide at Phe-18 by CTRC inhibited autoactivation of anionic trypsinogen, although cationic trypsinogen was strongly stimulated. Taken together, the observations indicate that human anionic trypsinogen is controlled by CTRC in a manner that individual natural mutations are unlikely to increase stability enough to promote intra-pancreatic activation. This unique biochemical property of anionic trypsinogen explains the lack of association of PRSS2 mutations with hereditary pancreatitis.

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Trypsinogen variants in pancreatic juice of healthy volunteers, chronic alcoholics, and patients with pancreatitis and cancer of the pancreas

Cited by 81 publications

References 10 publications

Biochemical Models of Hereditary Pancreatitis

Biochemical Models of Hereditary Pancreatitis

Identification and Expression of the cDNA-encoding Human Mesotrypsin(ogen), an Isoform of Trypsin with Inhibitor Resistance

Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

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