Disease relevance of PRSS2

• In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis [1].
• Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2) [2].
• Differential display of cDNAs expressed by human colorectal tumor tissues compared with adjacent normal colonic mucosa identified an isoform of TRY (TRY2) up-regulated in colorectal cancers [3].
• Human anionic trypsinogen: properties of autocatalytic activation and degradation and implications in pancreatic diseases [4].
• To elucidate possible evolutionary pathways leading to the loss of disulfide bonds, we have constructed mutants lacking one or two cysteines of four disulfide bonds (C22-C157, C127-C232, C136-C201, and C191-C220) in rat anionic trypsinogen and followed their expression in the periplasm of Escherichia coli [5].

High impact information on PRSS2

• Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease [1].
• Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)) [1].
• Its electrophoretic mobility and isoelectric pH lie between those of the cationic and anionic trypsinogen variants, and we propose the name "mesotrypsinogen" for the new enzyme precursor [6].
• Four serine protease gene fragments from this parasite were sequenced and one is 67% identical to the rat trypsin II gene [7].
• Mutations in anionic trypsinogen gene are not associated with tropical calcific pancreatitis [8].

Biological context of PRSS2

• Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six-year-old girl [9].
• PRSS1 and PRSS2 are located on chromosome 7q35, while PRSS3 is found on chromosome 9p13 [10].
• These data demonstrate that TRY2 is the dominant TRY in colon tissue and suggest that up-regulation of TRY1 expression in colon tumors may be associated with a metastatic phenotype [3].
• The deduced 259 and 267 amino acid sequences of Try2 and Chy1 show an identity of 33%-40% to trypsinogens and chymotrypsinogens of other insects [11].
• The genomic DNA of Try2 contains three introns and Chy1 contains five introns [11].

Anatomical context of PRSS2

• The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen [2].
• Homo sapiens possess several trypsinogen or trypsinogen-like genes of which three (PRSS1, PRSS2, and PRSS3) produce functional trypsins in the digestive tract [10].
• TRY2 mRNA was detected in all 6 colorectal tumor cell lines, whereas TRY1 mRNA was expressed only in the metastatic tumor lines, showing that the high levels of TRY expression in the metastatic tumor lines are likely due to up-regulation of TRY1 [3].
• In mixtures of cationic and anionic trypsinogen, an increase in the proportion of the anionic proenzyme had no significant effect on the levels of trypsin generated by autoactivation or by enterokinase at pH 8.0 in 1 mm Ca2+- conditions that were characteristic of the pancreatic juice [4].
• Immunoreactive cationic and anionic trypsinogen were continuously measured after the insertion of one probe inside the pig pancreas and another placed under the peritoneum on the anterior surface of the gland [12].

Associations of PRSS2 with chemical compounds

• After the previous characterization of one trypsin gene (Try1) of the human body louse Pediculus humanus, genes encoding a second trypsin (Try2) and a chymotrypsin (Chy1) have been cloned using degenerate serine proteinase primers and 5'- and 3'-RACE, and sequenced [11].

Regulatory relationships of PRSS2

• The Try2 gene was always expressed at much lower levels than Try1 or Chy1 [11].

Other interactions of PRSS2

• Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N29I had no such effect [2].
• RESULTS: Soweto controls had higher serum anionic trypsinogen (p = 0.004) and plasminogen activator:inhibitor ratio (p = 0.047) than U.K. controls [13].
• However, an assay for serum anionic trypsinogen is of no value as a test of pancreatic function in CF due to an apparent artifactual elevation of this enzyme in some patients [14].
• Urine was analyzed for anionic trypsinogen and the carboxypeptidase B activation peptide [13].
• The day after ERCP, higher concentrations of anionic trypsinogen, carboxypeptidase B activation peptide, IL-6, and polymorphonuclear elastase were recorded in the EIP group [15].

Analytical, diagnostic and therapeutic context of PRSS2

• To evaluate the relative contributions of 2 isoforms of TRY, TRY1 and TRY2, to total TRY mRNA expression, a semi-quantitative multiplex RT-PCR assay was developed [3].
• Using whole mount in situ hybridization, gene expression of Try1, Try2 and Chy1 has been localized not only in the distensible anterior region of the midgut of lice but sometimes also in the area following the distensible region [11].
• We have developed sensitive time-resolved immunofluorometric assays for the two trypsinogen isoenzymes, trypsinogen-1 and trypsinogen-2, which also are called cationic and anionic trypsinogen, respectively [16].
• Polymerase chain reaction (PCR)-amplified products of his cationic and anionic trypsinogen genes were examined by direct sequence analysis [17].
• Demonstration of human pancreatic anionic trypsinogen in normal serum by radioimmunoassay [18].

References