Pancreas and lipases

Neri et al89 reported the desymmetrization of A-Boc-serinol 98 by the selective monoacetylation using PPL (porcine pancreas lipase) and vinyl acetate as the acylating agent in organic solvent. The mono acetylated product (R)-99 was obtained after 2 hours with 99% ee and isolated in 69% chemical yield. Traces of the diacetylated product 100 were observed. The cyclization of (R)-99 in basic medium afforded the racemic oxazolidinone 101. The latter was subjected to enzymatic hydrolysis in phosphate buffer affording (R)-... 

Nature produces obviously not only interesting /1-lactams as in the antibiotics, but also structurally correspon ding jS-lactones. The high reactivity of the oxetanone system is crucial to the irreversible enzyme inhibition The oxetanone acylates a serine residue (Ser-152) in the active centre of the pancreas-lipase and thereby blocks its function (Fig. 5.110). [256] Some derivatives, e.g. tetrahydrolipstatin, also inhibit the thioesterase domain of the human fatty acid synthase. [257]... 

Enzymatic ring-opening copolymerization of structures 77 and 11 was performed in bulk at 100 °C using porcine pancreas lipase and/or Candida rugosa lipase as catalysts. 

Pancreatic lipase pancreas fats and other organic esters organic acid and alcohol (often gly ceroi) 7-0... 

Another approach to the synthesis of chiral non-racemic hydroxyalkyl sulfones used enzyme-catalysed kinetic resolution of racemic substrates. In the first attempt. Porcine pancreas lipase was applied to acylate racemic (3, y and 8-hydroxyalkyl sulfones using trichloroethyl butyrate. Although both enantiomers of the products could be obtained, their enantiomeric excesses were only low to moderate. Recently, we have found that a stereoselective acetylation of racemic p-hydroxyalkyl sulfones can be successfully carried out using several lipases, among which CAL-B and lipase PS (AMANO) proved most efficient. Moreover, application of a dynamic kinetic resolution procedure, in which lipase-promoted kinetic resolution was combined with a concomitant ruthenium-catalysed racem-ization of the substrates, gave the corresponding p-acetoxyalkyl sulfones 8 in yields... 

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. 

Lipases from porcine pancreas (PPL) and from Aspergillus niger are uniquely suited for oxazolone hydrolysis since they catalyze the ring-opening reaction with a high degree of enantioselectivity. Moreover, these lipases exhibited opposite stereochemical preference, thus providing access to both enantiomers of A -benzoyl... 

Lipases (triacyl glycerol acyl hydrolases, E.C 3.1.1.3) are a unique class of hydrolases for asymmetric synthesis86,87,S9,90e, They are available from fungi, bacteria and mammalians. The lipases most commonly used so far are the commercially supplied pig pancreas lipase (PPL)136, Pseudomonas cepacia lipase (PCL)89,137 and Candida cylindracea lipase (CCL). In most cases only the crude lipases, consisting of a mixture of proteins which may even be other hydrolases, are successfully applied1373. 

Exocrine pancreatic insufficiency is most commonly caused by cystic fibrosis, chronic pancreatitis, or pancreatic resection. When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired and can lead to steatorrhea, azotorrhea, vitamin malabsorption, and weight loss. Pancreatic enzyme supplements, which contain a mixture of amylase, lipase, and proteases, are the mainstay of treatment for pancreatic enzyme insufficiency. Two major types of preparations in use are pancreatin and pancrelipase. Pancreatin is an alcohol-derived extract of hog pancreas with relatively low concentrations of lipase and proteolytic enzymes, whereas pancrelipase is an enriched preparation. On a per-weight basis, pancrelipase has approximately 12 times the lipolytic activity and more than 4 times the proteolytic activity of pancreatin. Consequently, pancreatin is no longer in common clinical use. Only pancrelipase is discussed here. 

Although quite reliable empirical rules exist for the enantioselectivity of hydrolases for secondary alcohols (see Section 4.2.1.2), such rules are not as developed for primary alcohols, partly because many hydrolases often show low enantioselectivity. With some exceptions, lipases from Pseudomonas sp. and porcine pancreas lipase (PPL) often display sufficient selectivity for practical use. The model described in Figure 4.3 has been developed for Pseudomonas cepacia lipase (reclassified as Burkholderia cepacia), and, provided that no oxygen is attached to the stereogenic center, it works well for this lipase in many cases [41]. However, as soon as primary alcohols are resolved by enzyme catalysis, independent proof of configuration for a previously unknown product is recommended. 

Other microbial lipases have also been successfully used in anhydrous ionic liquids, e.g., from Alcaligenes sp. (AsL) [54, 58], CaLA, Rhizomucor miehei lipase (RmL), and Thermomyces lanuginosus lipase (TIL) [54]. The lipase from pig pancreas (porcine pancreas lipase, PPL), the only mammalian lipase that has been subjected to ionic liquids, catalyzed transesterificationin[BMIm][NTf2]butnotin[BMIm][PF6]... 

Hydrolytic enzymes Pancreatin Hydrolysis of starch (amylase), fat (lipase), and protein (protease) Porcine pancreas Digestive aid... 

The liver and the pancreas are not part of the digestive tract as such, but they provide enzymes and secretions required for digestion to occur in the small intestine. The pancreas secretes amylase, lipase, and nuclease enzymes, as well as several enzymes involved in breaking down proteins and peptides. As discussed below with digestion of fats, the liver secretes a substance called bUe that is stored in the gallbladder and then secreted into the duodenum when needed for digestion of fats. 

Four major enzyme groups are secreted lipolytic, proteolytic, amylolytic, and nucleic acid splitting enzymes. These pancreatic enzymes, some of which are secreted in multipile forms, possess specificities complementary to die intestinal membrane-bound enzymes (Tabic 1). Fresh, uncontsnkinated pancreatic juice is without proteolytic activity because these enzymes am in the form of inactive zymogens. An important fraction of the calcium in pancreatic juice accompanies the enzymes, especially ct-amylase. Human pancreatic juice is moat dose to that of the pig, with high proportions of lipase and a-amylase in comparison with other mammals [1]. Therefore, pig pancreas extract, pancreatin, has up to now been die oreferred enzvme source for therapeutic tuncreas substitution. 

Relevant quality control should not be restricted to the usual triad of activities of pancreas lipase, a-amylase, and trypsin, but should be extended to the content of colipasc, the activities of the two other lipolytic enzymes present in pancreatine (phospholipase Aj and carboxylester lipase), and the dissolution characteristics of enteric-coated preparations as a function of time and pH (Fig. 16). The availability of such information will certainly contribute to a better tailoring of flic management of maldigestion in the individual patient and to a more appropriate correction of the obligate nonphysio logical route of delivery of these enzyme supplements. 

Absorption of fat in the newborn, and particularly in premature infants, is much less efficient than in adults due to the relatively low output of lipase and bile salts from the pancreas of the infant. Intragastric lipolysis by milk BSSL and lingual or salivary lipases, the secretion of which is stimulated by suckling, appears to augment the pancreatic lipase system in the newborn (Hamosh, 1979 Hernell and Blackberg, 1994). 

Pancreas Lipase, Both are cleared by the kidney and hence are elevated... 

As early as 1984 the porcine pancreas lipase-catalysed enantioselective synthesis of (R)-glycidol was described. At pH 7.8 and ambient temperatures the reaction was allowed to proceed to 60% conversion (Scheme 6.9). This means that the enzyme was not extremely enantioselective, otherwise it would have stopped at 50% conversion. Nonetheless, after workup the (R)-glycidol was obtained in a yield of 45% with an ee of 92% [42]. This was a remarkable achievement and the process was developed into an industrial multi-ton synthesis by Andeno-DSM [34, 43]. While on the one hand a success story, it also demonstrated the shortcomings of a kinetic resolution. Most enzymes are not enantiospecific but enantioselective and thus conversions do not always stop at 50%, reactions need to be fine-tuned to get optimal ees for the desired product [28]. As mentioned above kinetic resolutions only yield 50% of the product, the other enantiomer needs to be recycled. As a result of all these considerations this reaction is a big step forward but many steps remain to be done. 

The pancreas secretes a variety of enzymes into the gut. These include proteolytic enzymes, such as trypsin and chymotrypsin, lipase and amylase. The salivary glands also produce an amylase. The major hormones produced by the pancreas are insulin, glucagon and somatostatin. 

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