Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation.

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Citation

Teich N, Ockenga J, Hoffmeister A, Manns M, Mossner J, Keim V

Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation.

Gastroenterology. 2000 Aug;119(2):461-5.

PubMed ID
10930381 [ View in PubMed
]
Abstract

BACKGROUND & AIMS: Mutations of the cationic trypsinogen have been described in hereditary pancreatitis. We report a new trypsinogen mutation in the activation peptide of the proenzyme in a family with chronic pancreatitis. METHODS: The coding region of the cationic trypsinogen gene was sequenced after polymerase chain reaction amplification. The following peptides homologous to the N-terminal end of cationic trypsinogen were synthesized (one-letter code, mutated amino acid underlined): wild-type peptide, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; pK23R, APFDDDDRIVGG. The sequences of pD22G and pK23R correspond to the recently identified mutation K23R and to the mutation described here (D22G). To mimic trypsinogen activation, these peptides were digested with trypsin for 30 minutes at pH 5.0-8. 0, and the fragments were analyzed by high-performance liquid chromatography. RESULTS: In a family with clinical evidence of hereditary chronic pancreatitis, a missense mutation of codon 22 (GAC-->GGC) of the cationic trypsinogen was found. This mutation results in a substitution of aspartic acid by glycine; therefore, the mutation was called D22G. Chromatographic analysis of tryptic digests of the peptides pD22G and pK23R showed hydrolysis rates of 22% and 75%, respectively, whereas the wild-type peptide was hydrolyzed at only 6%. The cleavage rates were reduced at lower pH, and no hydrolysis occurred without trypsin. CONCLUSIONS: The activation peptides of the trypsinogen variants D22G and K23R could be released at a higher rate than in wild-type trypsinogen, resulting in increased amounts of trypsin in the pancreas, which could initiate pancreatitis.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Trypsin-1P07477Details