36 Here, we review the biochemical studies on the function of CTRC in digestive enzyme regulation, the genetic variants in CTRC, the functional effects of CTRC variants, and discuss the potential mechanism of action of CTRC variants as risk factors for chronic pancreatitis. The CTRC gene (Online Mendelian Inheritance in Men *601405) is located on chromosome 1p36.21 and comprises eight exons spanning 8.2 kb. The human CTRC primary translation

product (pre-chymotrypsinogen C) is composed of a secretory signal peptide of 16 amino acids, a propeptide (activation peptide) of 13 amino acids, and a MI-503 chymotrypsin-like enzyme of 239 amino acids. CTRC is a digestive protease synthesized and secreted this website by the pancreatic acinar cells as an inactive proenzyme (zymogen), which becomes activated in the duodenum after tryptic cleavage of the Arg29–Val30

peptide bond at the C-terminal end of the propeptide. CTRC was first isolated from the pig pancreas and was found to cleave after Phe, Tyr, Leu, Met, Gln, and Asn amino acid residues, showing chymotrypsin-like substrate specificity, with characteristically higher activity on leucyl peptide bonds, both in synthetic and natural substrates.38–40 However, human CTRC is found in the vicinity of the ELA2A and ELA2B genes, and the extent of sequence identity between human CTRC and ELA2A is higher than that between CTRC and CTRB1 or CTRB2. In the pancreatic juice of ruminants, chymotrypsinogen C is found in ternary complex with procarboxypeptidase A (proCPA) and proproteinase E, or in binary complex with proCPA.41–43 The crystal structure of the ternary complex has been determined.43 The substrate specificity of the activated and chemically dissociated active bovine CTRC was similar to its porcine ortholog.44 CTRC is almost certainly the same protein as caldecrin, a serum–calcium-decreasing protein isolated from porcine and rat pancreas, and later cloned from rat and human pancreas, although the identity of these two proteins has not been demonstrated formally.45–47 Caldecrin

was also found to inhibit osteoclast activation and bone resorption.48 MCE The protease activity of CTRC and its effect on calcium homeostasis appear to be distinct and unrelated functions, although both require activation by trypsin. The first indication that CTRC is not only a digestive enzyme, but also plays a role in regulating the activity of other digestive enzymes, came from the discovery that CTRC stimulates autoactivation of human cationic trypsinogen.49 Activation of trypsinogen to trypsin involves the proteolytic removal of the trypsinogen activation peptide by cleavage of the Lys23–Ile24 peptide bond, a process physiologically catalyzed by the serine protease enteropeptidase in the duodenum.