Comparative Pepstatin Inhibition Studies on Individual Human Pepsins and Pepsinogens 1,3 and 5(gastricsin) and Pig Pepsin A

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 18; no. 3; pp. 209 - 217
• Main Authors: Roberts, N.B., Taylor, W.H.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 01.06.2003; Taylor & Francis
• Subjects: Animals; Anti-Ulcer Agents - pharmacology; Binding Sites; Carbenoxolone - pharmacology; Chromatography, Gel; Crystallography, X-Ray; Dextrans - pharmacology; Dose-Response Relationship, Drug; Humans; Hydrogen-Ion Concentration; Indicators and Reagents - pharmacology; Inhibition; Kinetics; Models, Molecular; Pepsin A - antagonists & inhibitors; Pepsin A - chemistry; Pepsinogens; Pepsins 1,3,5(gastricsin); Pepstatin; Pepstatins - chemistry; Pepstatins - pharmacology; Protein Binding; Protein Conformation; Swine
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/1475636031000076888

Human gastric juice contains 3 major proteolytic components (pepsins1,3 and 5 or gastricsin). Pepsin 1 is increased in peptic ulcer and it's properties are relatively poorly understood. Studies with pepstatin the highly specific aspartic-protease inhibitor have therefore been carried out on individual active and proenzymes to assess any enzymic similarities. Human pepsin 1 was inhibited with high affinity similar to pepsin 3, whereas pepsin 5(gastricsin) was at least 40 times less sensitive. Inhibition of human pepsinogens 1,3 and 5 and pig pepsinogen A showed similar trends to the active enzymes. Studies using Sephadex gel filtration showed that pepstatin does not bind to pepsinogens and inhibition arises from pepstatin binding the pepsins released upon activation. Pepstatin inhibition was shown to be relatively independent of pH between 1.5 and 3.8 although at higher pH inhibition was less effective. The evidence suggests that pepsin 1 is similar to pepsin 3 and pepstatin inhibits by a one to one molecular binding to the active site. The explanation for the reduced affinity of pepstatin to pepsin 5(gastricsin) needs further study by co-crystallisation X-ray analysis.