Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway

Abstract

Genetic investigations have provided unique insight into the mechanism of chronic pancreatitis in humans and firmly established that uncontrolled trypsin activity is a central pathogenic factor. Mutations in the PRSS1, SPINK1, and CTRC genes promote increased activation of trypsinogen to trypsin by stimulation of autoactivation or by impairing protective trypsinogen degradation and/or trypsin inhibition. Here we review key genetic and biochemical features of the trypsin-dependent pathological pathway in chronic pancreatitis.

Keywords: Chymotrypsin; Digestive enzymes; Pancreas; Pancreatitis; Trypsin inhibitor; Trypsinogen activation.

Fig. 1

Trypsin-dependent pathological pathway in chronic pancreatitis. Activation of PRSS1 trypsinogen to active trypsin in the pancreas is responsible for disease onset and progression. Protective mechanisms to control trypsinogen activation include trypsin inhibition by SPINK1 and trypsinogen degradation by chymotrypsin C (CTRC) and trypsin. CTRC cleaves the Leu81-Glu82 peptide bond, and trypsin cleaves the Arg122-Val123 peptide bond; the combination of these two cleavages results in irreversible trypsinogen degradation. CTRC also stimulates autoactivation of cationic trypsinogen by cleaving the Phe18-Asp19 peptide bond in the activation peptide. The shortened activation peptide is more susceptible to trypsin-mediated activation at the Lys23-Ile24 peptide bond. The indicated hereditary pancreatitis-associated PRSS1 mutations increase trypsinogen autoactivation by inhibition of CTRC-dependent trypsinogen degradation (red arrow) or by increasing CTRC-dependent stimulation of autoactivation (green arrow, mutations in orange type). Activation peptide mutations directly stimulate autoactivation independently of CTRC function (green arrow, mutations in black type). Loss-of-function mutations in SPINK1 reduce inhibitor expression and thus compromise trypsin inhibition. Loss-of function mutations in CTRC reduce secretion, block zymogen activation, diminish catalytic activity or promote degradation by trypsin, and therefore impair protective trypsinogen degradation. p.insIDK indicates mutation p.K23_I24insIDK. Figure modified from Ref. [8]

Fig. 2

Schematic representation of the effect of the SPINK1 trypsin inhibitor on the autoactivation of PRSS1 trypsinogen. Note that SPINK1 delays autoactivation but has no effect on final trypsin levels

Fig. 3

Schematic representation of the effect of CTRC on the autoactivation of PRSS1 trypsinogen. CTRC slightly accelerates the onset of autoactivation but markedly reduces final trypsin levels through trypsinogen degradation