Lipoprotein lipase treatment

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Milk is clarified by high-speed centrifugation to remove extraneous matter held in suspension. Clarification occurs prior to heat treatment of the milk to prevent dissolution of the extraneous matter. Although clarification removes somatic cells, the elevated levels of lipoprotein lipase activators and plasmin that may be associated with increased numbers of white blood cells in the milk are not eliminated. Therefore, increased lipolysis of milk fat by lipoprotein lipase and proteolysis of casein by plasmin may not be deterred. 

The enzymes responsible for the detrimental effects of lipolysis are of two main types those indigenous to milk, and those of microbial origin. The major indigenous milk enzyme is lipoprotein lipase. It is active on the fat in natural milk fat globules only after their disruption by physical treatments or if certain blood serum lipoproteins are present. The major microbial lipases are produced by psychrotrophic bacteria. Many of these enzymes are heat stable and are particularly significant in stored products. 

Other factors. A cow s hormonal balance can affect the susceptibility of her milk to spontaneous lipolysis (Fredeen et al., 1951 Kastli et al., 1967 Bachman et al., 1988). The oestrus cycle appears to have little effect on spontaneous lipolysis (Fredeen et al, 1951) but may affect lipase activity in the milk (Kelly, 1945). In contrast, treatment of cows with oestradiol and progesterone has been shown to lead to increased lipolysis in the milk (Bachman, 1982 Heo, 1983 Bachmann eta/., 1985) but no change (Bachman, 1982) or a transient increase (Bachmann et al., 1985) in total lipase activity. It appears that the increased lipolysis in milk following hormonal treatment, or in milk from cows with ovarian cysts, may not be typical spontaneous lipolysis as cooling is not needed to initiate it (Bachman, 1982) a lipase other than lipoprotein lipase, possibly a bile salt-stimulated lipase, may be responsible for such lipolysis (Heo, 1983 Bachmann et al., 1985). Treatment of cows with bovine somatotropin has been reported to have no significant effect on milk lipoprotein lipase activity (Azzara et al., 1987). 

Lipolysis is important from the standpoint of the qnality of milk and dairy products. The natural lipoprotein lipase in milk is the main agent in the lipolysis of raw milk. In dairy products, hydrolytic rancidity is primarily cansed by heat-stable lipases prodnced by psychrotrophic bacteria or by residnal native lipase that survived heat treatment. The milk lipase and most bacterial lipases preferentially attack the FA residnes in the terminal positions. Becanse milk fat contains relatively high proportions of short-chain FA, which are esterified in the in-3-position, lipolysis increases the level of these FA in free form. The short-chain FA are solnble in water and they may be present in dissociated form (salts) or associated form (acid form), depending on the pH of the aqueous phase of the milk product. The characteristic lipolytic flavors occur when the acids are present in the acid form. Some FA have low flavor thresholds, and even very small amonnts canse an unpleasant, rancid flavor of milk and dairy products. Only in some types of cheese (e.g., mold cheeses) is moderate lipolysis desirable for specific flavor. 

High serum levels of triglyceride (TG)-rich lipoproteins, i.e. very low density lipoproteins (VLDL) and its remnants are important risk factors for coronary artery disease. Serum TGs can be lowered either by dietary treatment with fish oils or by pharmacological treatment with drugs of the fibrate class. Classically, the decrease in plasma TG concentrations upon fibrate treatment (Table 1) are thought to be the result of a decreased hepatic secretion of VLDL accompanied by an enhanced plasma TG clearance, possibly due to the induction of lipoprotein lipase (LPL) activity in peripheral tissues. ... 

Another interesting innovation is the registration of alipogene tiparvovec, it represents the first gene therapy treatment that has reached the market [15]. The medicinal product consists of the human lipoprotein lipase gene that is encapsulated in a vector derived from adeno-associated vims (AAV), serotype 1. The viral vector will deliver the gene into the cell, in this case a muscle cell, where the gene can be expressed after which the lipoprotein lipase is produced, fii... 

A fall in ) -lipoprotein and, particularly. TG concentrations in hyperlipaemic patients with frequent increase of a-lipoprotein is observed after heparin treatment at doses activating lipoprotein lipase, an enzyme which catalyses the hydrolysis of TG. 

Chiesa G, Michelagnoli S, Cassinotti M, Gianfranceschi G, Werba JP, Paz-zucconi F, et al. Mechanisms of high-density lipoprotein reduction after probu-col treatment changes in plasma cholesterol esterification/transfer and lipase activities. Metabolism 1993 42 229-235. 

Lipoprotein associated phospholipase A2(LpPLA2> is a serine dependent lipase of novel structure which is associated with the presence of LDL in plasma. It hydrolyses oxidised phospholipids to generate lysophosphatidylcholine and oxidised free fatty acids (Scheme 1), both of which are potent chemoattractants for circulating monocytes. Accumulation of lysophosphatidylcholine results in macrophage proliferation and the endolithial dysfunction observed in patients with atherosclerosis. Inhibition of LpPLA2 would thus be expected to stop plaque build-up and provide an attractive strategy in the treatment of atherosclerosis. 

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