Pancreatitis lipase and

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas characterized by severe pain in the upper abdomen and increased serum concentrations of pancreatic lipase and amylase. 

Jensen, R. G., Sampugna, J. and Pereira, R. L. 1964. Intermolecular specificity of pancreatic lipase and the structural analysis of milk triglycerides. J. Dairy Sci. 47, 727-732,... 

Cotterill, I. C. Sutherland, A. G. Robert, S. M. Grobbauer, R. Spreitz, J. Faber, K. Enzymatic resolution of sterically demanding bicyclo[3.2.0]heptanes evidence for a novel hydrolase in crude porcine pancreatic lipase and the advantages of using organic media for some of the biotransformations. J. Chem. Soc. Perkin Trans 1991, 1, 1365. 

In the intestine, dietary fats are hydrolyzed by pancreatic lipase and the released fatty acids taken up into the intestinal cells. Both the digestion and uptake processes are aided by the detergent-like properties of the bile salts (see Topic K5). 

Lipstatin 118 and tetrahydrolipstatin 119 are well known to be potent inhibitors of pancreatic lipase and as such they have potential therapeutic properties as antiobesity drugs. Research in recent years has been focused on finding efficient stereoselective routes for the synthesis of (-)-tetrahdyrolipstatin, (—)-119, which is now marketed as the... 

The three dimensional structures of human pancreatic Lipase and Rhizo-mucor miehei lipase have recently been elucidated 1141-1431. Among the lipases purified foam different sources—mammals, bacteria, fungi, and plants-—the fungal lipases from Rhizopuj species exhibit a remarkably broad pH zone of stability and activity, extending from pH 3 to 9. 

H. Brockerhoff. A model of pancreatic lipase and the orientation of enzymes at interfaces. Chem. Phyz Lipids 10 113 (1973). 

P. Desnuelle. Pancreatic lipase and phospholipase. In Molecular and Cellular Basis of Digestion (P. Desnuelle, J- SjGstrHm, and O. Novin, eds.). Elsevier, Amsterdam, 1986,00.275-296. 

Perez de la Cruz Moreno M, Oth M, Deferme S, Lammert F, Tack J, Dressman J and Augustijns P (2006) Characterization of fasted-state human intestinal fluids collected from duodenum and jejunum. J Pharm Pharmacol 58(8) 1079-1089 Reboul E, Berton A, Moussa M, Kreuzer C, Crenon I and Borel P (2006) Pancreatic lipase and pancreatic lipase-related protein 2, but not pancreatic lipase-related protein 1, hydrolyze retinyl palmitate in physiological conditions. Biochim Biophys Acta 1761(1 ) 4—10 Scheele G, Bartelt D and Biegzr W (1981) Characterisation of human exocrine pancreatic proteins. Gastroent 80(3) 461 473... 

The (3-monoglycerides formed are resistant to further hydrolysis. This pattern is characteristic of pancreatic lipase and has been used to study the triglyceride structure of many fats and oils. 

Specificity for certain fatty acids by some lipolytic enzymes has been demonstrated. Pancreatic lipase and milk lipase are broad-spectrum enzymes and show no specificity for any of the fatty acids found in fats. Instead, the fatty acids that are released from... 

About 70% to 90% of dietary retinol is absorbed, and, even at high intakes, this falls only slightly. Retinyl esters are hydrolyzed by pancreatic lipase and... 

Cytochrome exists in a soluble form in erythrocytes and in a membrane bound form in microsomes. A soluble derivative of hepatic cyt bs with 93 amino acids can be isolated by treatment of microsomes with pancreatic lipase and this form has essentially the same amino acid sequence as the erythrocyte protein. Further treatment of the soluble form with trypsin cleaves two residues from the N-terminal and seven from the carboxylate-terminal and leaves the heme core with only 84 residues. Rat liver cyt b has been prepared by expression in Eschericha coli (E.coli). The structure of... 

In the remainder of the paper, I concentrate on the two best-known lipolytic enzymes—pancreatic lipase and phospholipase 2—and then speculate on the special nature of lipolytic reactions and how lipolytic enzymes diflFer from hydrolases. 

Lipstatin (58), comprised of a 3,5-dihydroxy-2-hexyl hexadeca-7,9-dienoic acid with cyclization of the hydroxy group at C-3 with the carboxylic acid to form a P-lactone and esterification of the hydroxy group at C-5 with a A-formyl leucine, was isolated from Streptomyces toxytricini. It inhibits gastric and pancreatic lipase and blocks intestinal absorption of lipids (40, 41). Reduction of the olefins led to the synthesis of tetrahydrolipstatin, which was approved in 1999 as Xenical (59) for the treatment of obesity (42-44). 

In neonate, suckling mammals, short- and medium-chain fatty acids are preferentially split at the sn-3 triacylglycerol position by oral and gastric lipases and are absorbed in the stomach, while the long-chain fatty acids are hydrolyzed at the sn- and sn-2 positions and by pancreatic lipases and are absorbed in the small intestine (50, 51). With growth, the neonate fat digestion system becomes less active, and is replaced by the small intestine-pancreatic lipase pathway. But residual oral and gastric lipase activities and direct absorption of short-chain fatty acids in the... 

The digestion of triacylglycerols in adult nonruminant mammals has been described as initiated in the mouth by hngual lipase released in the sahva at the base of the tongue (52). Up to 6% of the fatty acids are hydrolyzed and initiate emulsion formation in the stomach. The digesta (called chyme at this location) is released from the stomach slowly into the duodenum to ensure complete mixing with the bile salts and emulsification. Lipolysis occurs by association of pancreatic lipase and co-lipase at the surface of the bile salt-stabihzed emulsion. Amphipathic molecules (fatty acids, sn-2 monoacylglycerols, and lysolecithins) are produced and associate with the bile salts to form water-soluble micelles from which absorption occurs. 

Lipstatin is a natural product that exhibits potent inhibitor activity of the pancreatic lipase, and therefore it is a potential lead for the development of antiobesity agents. P.J. Kocienski developed a synthesis for this compound that incorporates an aldehyde-ketene cycloaddition as the key step. The reaction between the aldehyde and silylketene derivative was carried out in the presence of EtAICIs that served as the Lewis acid activator. This transformation led to the formation of four diastereomers in 91% yield, but after desilylation, the desired stereoisomer could be isolated in 64% yield from the mixture. 

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