Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen.

Abstract

Trypsin-mediated trypsinogen activation (autoactivation) facilitates digestive zymogen activation in the duodenum but may precipitate pancreatitis if it occurs prematurely in the pancreas. Autoactivation of human cationic trypsinogen is inhibited by a repulsive electrostatic interaction between the unique Asp218 on the surface of cationic trypsin and the conserved tetra-aspartate (Asp19-22) motif in the trypsinogen activation peptide (Nemoda, Z., and Sahin-Tóth, M. (2005) J. Biol. Chem. 280, 29645-29652). Here we describe that this interaction is regulated by chymotrypsin C (caldecrin), which can specifically cleave the Phe18-Asp19 peptide bond in the trypsinogen activation peptide and remove the N-terminal tripeptide. In contrast, chymotrypsin B, elastase 2A, or elastase 3A (proteinase E) are ineffective. Autoactivation of N-terminally truncated cationic trypsinogen is stimulated approximately 3-fold, and this effect is dependent on the presence of Asp218. Because chymotrypsinogen C is activated by trypsin, and chymotrypsin C stimulates trypsinogen activation, these reactions establish a positive feedback mechanism in the digestive enzyme cascade of humans. Furthermore, inappropriate activation of chymotrypsinogen C in the pancreas may contribute to the development of pancreatitis. Consistent with this notion, the pancreatitis-associated mutation A16V in cationic trypsinogen increases the rate of chymotrypsin C-mediated processing of the activation peptide 4-fold and causes accelerated trypsinogen activation in vitro.

• Authors: Zsófia Nemoda, Miklós Sahin-Tóth
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 17 Pg. 11879-86 (Apr 28 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16505482 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cations
• Peptide Fragments
• Trypsinogen
• Chymotrypsin
• chymotrypsin C
• Trypsin

Topics

• Cations (chemistry)
• Cells, Cultured
• Chymotrypsin (pharmacology)
• Enzyme Activation
• Humans
• Kidney (metabolism)
• Pancreatic Juice (metabolism)
• Peptide Fragments (metabolism)
• Trypsin (pharmacology)
• Trypsinogen (chemistry, metabolism)