Human anionic trypsinogen. Properties of autocatalytic activation and degradation and implications in pancreatic diseases

Z. Kukor, Miklós Tóth, Miklós Sahin-Tóth

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Human pancreatic secretions contain two major trypsinogen isoforms, cationic and anionic trypsinogen, normally at a ratio of 2:1. Pancreatitis, pancreatic cancer and chronic alcoholism lead to a characteristic reversal of the isoform ratio, and anionic trypsinogen becomes the predominant zymogen secreted. To understand the biochemical consequences of these alterations, we recombinantly expressed and purified both human trypsinogens and documented characteristics of autoactivation, autocatalytic degradation and Ca2+-dependence. Even though the two trypsinogens are ≈ 90% identical in their primary structure, we found that human anionic trypsinogen and trypsin exhibited a significantly increased (10-20-fold) propensity for autocatalytic degradation, relative to cationic trypsinogen and trypsin. Furthermore, in contrast to the characteristic stimulation of the cationic proenzyme, acidic pH inhibited autoactivation of anionic trypsinogen. 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. In contrast, rates of trypsinogen activation were markedly reduced with increasing ratios of anionic trypsinogen under conditions that were typical of potential sites of pathological intra-acinar trypsinogen activation. Thus, at low Ca2+ concentrations at pH 8.0, selective degradation of anionic trypsinogen and trypsin caused diminished trypsin production; while at pH 5:0, inhibition of anionic trypsinogen activation resulted in lower trypsin yields. Taken together, the observations indicate that up-regulation of anionic trypsinogen in pancreatic diseases does not affect physiological trypsinogen activation, but significantly limits trypsin generation under potential pathological conditions.

Original languageEnglish
Pages (from-to)2047-2058
Number of pages12
JournalEuropean Journal of Biochemistry
Volume270
Issue number9
DOIs
Publication statusPublished - May 2003

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Trypsinogen
Pancreatic Diseases
Chemical activation
Degradation
Trypsin
Enzyme Precursors
Protein Isoforms
Enteropeptidase
Pancreatic Juice

Keywords

  • Alcoholic pancreatitis
  • Anionic trypsin
  • Autoactivation
  • Autolysis
  • Cationic trypsin

ASJC Scopus subject areas

  • Biochemistry

Cite this

Human anionic trypsinogen. Properties of autocatalytic activation and degradation and implications in pancreatic diseases. / Kukor, Z.; Tóth, Miklós; Sahin-Tóth, Miklós.

In: European Journal of Biochemistry, Vol. 270, No. 9, 05.2003, p. 2047-2058.

Research output: Contribution to journalArticle

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