Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrahydrolipstatin is a specific lipase inhibitor derived from lipstatin, a lipid produced by Streptomyces toxytricini. In addition to pancreatic lipase, it is shown in the present study that tetrahydrolipstatin also inhibits human gastric lipase, carboxyl ester lipase (cholesterol esterase) of pancreatic origin and the closely related bile-salt-stimulated lipase of human milk. It does not inhibit the exocellular lipase from Rhizopus arrhizus or a lipase recently isolated from Staphylococcus aureus. In the presence of a water-insoluble substrate, such as tributyrin, the inhibition has the characteristics of an irreversible inactivation of the uncompetitive type, thus indicating that an enzyme.substrate.inhibitor complex is formed, which cannot undergo further reaction to yield the normal product. This reaction probably takes place at the aqueous/oil interface of the substrate. In aqueous solution, in the absence of substrate, the inhibition of carboxyl ester lipase by tetrahydrolipstatin has the characteristics of being reversible, and finally becomes of a temporary nature analogues to the trypsin-trypsin inhibitor system. It is suggested that an enzyme-inhibitor complex of an acyl-enzyme type is formed that is slowly hydrolysed, with water as the final acceptor, leaving an intact enzyme and an inactive form of the inhibitor. The enzyme thus consumes the inhibitor, which undergoes a chemical conversion, as indicated by a change in mobility in an appropriate thin-layer chromatographic system, indicating an increase in hydrophilicity. Evidence is presented that the reaction product is an acid and that the functional group of tetrahydrolipstatin is the beta-lactone reacting with the active site of the enzyme.
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PMID:Mode of action of tetrahydrolipstatin: a derivative of the naturally occurring lipase inhibitor lipstatin. 316 82

Gastric and pancreatic lipases are enzymes that play a pivotal role in the digestion of dietary fat. Orlistat, a semisynthetic derivative of lipstatin, is a potent and selective inhibitor of these enzymes, with little or no activity against amylase, trypsin, chymotrypsin and phospholipases. It exerts its effect within the gastrointestinal (GI) tract. Orlistat acts by binding covalently to the serine residue of the active site of gastric and pancreatic lipases. When administered with fat-containing foods, orlistat partially inhibits hydrolysis of triglycerides, thus reducing the subsequent absorption of monoaclglycerides and free fatty acids. This effect can be measured using 24h faecal fat excretion as a representative pharmacodynamic parameter. Orlistat's pharmacological activity is dose-dependent and can be described by a simple Emax model which exhibits an initial steep portion of the dose-response curve with a subsequent plateau (approximately 35% inhibition of dietary fat absorption) for doses above 400 mg/d. At therapeutic doses (120 mg tid with main meals) administered in conjunction with a well balanced, mildly hypocaloric diet, the inhibition of fat absorption (approximately 30% of ingested fat) contributes to an additional caloric deficit of approximately 200 calories. Orlistat does not produce significant disturbances to GI physiological processes (gastric emptying and acidity, gallbladder motility, bile composition and lithogenicity) or to the systemic balance of minerals and electrolytes. Similarly, orlistat does not affect the absorption and pharmacokinetics of drugs with a narrow therapeutic index (phenytoin, warfarin, digoxin) or compounds frequently used by obese patients (oral contraceptives, glyburide, pravastatin, slow-release nifedipine).
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PMID:Mode of action of orlistat. 922 72

The role of lipase in the regulation of upper gastrointestinal function is poorly understood. We studied the effect of orlistat, a new, potent, and highly specific lipase inhibitor, on gastric emptying, cholecystokinin (CCK) release, and pancreaticobiliary secretion. Three groups of studies were performed in nine healthy volunteers, using the double-indicator technique with a triple-lumen duodenal tube, polyethylene glycol 4000 as a duodenal perfusion marker, and 99mTc-diethylenetriamine pentaacetic acid as a meal marker. Gastric emptying, pancreaticobiliary output, and postprandial plasma CCK levels were measured after ingestion of the following isocaloric 500-ml liquid meals with or without 200 mg orlistat: 1) a pure fat meal (10% Intralipid), 2) a meal containing free fatty acids, or 3) an albumin-glucose meal. All experiments were performed in a randomized, placebo-controlled, crossover design. Orlistat markedly inhibited lipase activity in all three experiments. Orlistat given with the fat meal reduced CCK release and output of lipase, trypsin, and bilirubin and accelerated the rate of gastric emptying (P < 0.05). After ingestion of the free fatty acid or albumin-glucose meal, orlistat had no significant effect on any of these parameters. We conclude that lipase plays an important, nutrient-specific role in the regulation of gastric emptying and pancreaticobiliary secretion after ingestion of fatty meals in humans.
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PMID:Role of lipase in the regulation of upper gastrointestinal function in humans. 931 63