(Below N is a link to NCBI taxonomic web page and E link to ESTHER at designed phylum.) > cellular organisms: NE > Eukaryota: NE > Opisthokonta: NE > Metazoa: NE > Eumetazoa: NE > Bilateria: NE > Deuterostomia: NE > Chordata: NE > Craniata: NE > Vertebrata: NE > Gnathostomata: NE > Teleostomi: NE > Euteleostomi: NE > Sarcopterygii: NE > Dipnotetrapodomorpha: NE > Tetrapoda: NE > Amniota: NE > Mammalia: NE > Theria: NE > Eutheria: NE > Boreoeutheria: NE > Euarchontoglires: NE > Glires: NE > Rodentia: NE > Myomorpha: NE > Muroidea: NE > Cricetidae: NE > Cricetinae: NE > Mesocricetus: NE > Mesocricetus auratus: NE
LegendThis sequence has been compared to family alignement (MSA) red => minority aminoacid blue => majority aminoacid color intensity => conservation rate title => sequence position(MSA position)aminoacid rate Catalytic site Catalytic site in the MSA MGRLEILFLGLTCCLAAACAAKLGTVYTEGGFVEGVNKKLSLLGGDSVDV FKGIPFATAKTLENPQRHPGWQGTLQAKDFKKRCLQATITQDNTYGQEDC LYLNIWVPQSRKQVSENLPVMVWIYGGAFLMGAGHGANFLKNYLYDGEEI ATRGNVIVVTFNYRVGPLGFLSTGDANLPGNFGLRDQHMAIAWVKRNIAA FGGDPDNITIFGESAGGASVSLQTLSPYNKGLIRRAISQSGVSLSPWAIQ KNPLSWAQKIAKKVGCPTDDTSKLAGCLKVTDPRALTLAYKLPLTSQEYP IEHYLGFTPVVDGDFIPDDPINLYANAADVDYLAGTNDMDGHLFATVDVP AIDKTKQDVTEEDFYKLVRGYTISKGLKGAQSTYNIYTESWAQDPSQENK KKTVVAFETDTLFLIPTEMALVQHKANAKSGKTYSYLFSYPSRMPIYPKW MGADHADDLQYVFGKPFATPLGYRAQDRTLSKAMIAYWTNFARSGDPNMG NSPVPTHWYPYTLENGNYLDITKAITSTSMKEHLRAKFLKFWTVTFEVLP TVTDDQ
BACKGROUND: Pancreatic cholesterol esterase has three proposed functions in the intestine: 1) to control the bioavailability of cholesterol from dietary cholesterol esters; 2) to contribute to incorporation of cholesterol into mixed micelles; and 3) to aid in transport of free cholesterol to the enterocyte. Inhibitors of cholesterol esterase are anticipated to limit the absorption of dietary cholesterol. RESULTS: The selective and potent cholesterol esterase inhibitor 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyrone (figure 1, structure 1) was administered to hamsters fed a high cholesterol diet supplemented with radiolabeled cholesterol ester. Hamsters were gavage fed 3H-labeled cholesteryl oleate along with inhibitor 1, 0-200 micromoles. Twenty-four hours later, hepatic and serum radioactive cholesterol levels were determined. The ED50 of inhibitor 1 for prevention of the uptake of labeled cholesterol derived from hydrolysis of labeled cholesteryl oleate was 100 micromoles. The toxicity of inhibitor 1 was investigated in a 30 day feeding trial. Inhibitor 1, 100 micromoles or 200 micromoles per day, was added to chow supplemented with 1% cholesterol and 0.5% cholic acid. Clinical chemistry urinalysis and tissue histopathology were obtained. No toxicity differences were noted between control and inhibitor supplemented groups. CONCLUSIONS: Inhibitors of cholesterol esterase may be useful therapeutics for limiting cholesterol absorption.
Title: Lipid-lowering effects of WAY-121,898, an inhibitor of pancreatic cholesteryl ester hydrolase Krause BR, Sliskovic DR, Anderson M, Homan R Ref: Lipids, 33:489, 1998 : PubMed
WAY-121,898 is an inhibitor of pancreatic cholesteryl ester hydrolase (pCEH). After confirming its in vitro potency and relative lack of a major effect on acyl-CoA:cholesterol acyltransferase (ACAT), it was found that this compound lowers plasma cholesterol in cholesterol-fed, but not chow-fed, rats. Measures of liver cholesteryl ester content and the direct determination of cholesterol absorption (lymph-fistula model) show that inhibition of cholesterol absorption is at least one mechanism for the observed cholesterol lowering. However, WAY-121,898 was also active when administered parenterally to cholesterol-fed rats, and in cholesterol-fed hamsters cholesterol-lowering occurred with oral dosing despite no change in cholesterol absorption, suggesting other modes of action possibly relating to inhibition of liver CEH. Combination treatment in cholesterol-fed rats with the ACAT inhibitor CI-976 resulted in a greater-than-additive reduction in plasma cholesterol, implying that both pCEH and ACAT may play a role in cholesterol absorption in this species. In rabbits, WAY-121,898 prevented the rise in plasma cholesterol due to the feeding of cholesteryl ester but not in rabbits fed (free) cholesterol. In guinea pigs, the compound induced an increase in adrenal cholesteryl ester mass. Taken together, the overall profile in these animal models suggests that WAY-121,898 inhibits more than just the intestinal (lumenal) pCEH, and that the role of this enzyme in cholesterol metabolism may be different within and across species, the former depending upon the dietary cholesterol load.
Title: Established and Emerging Strategies for Inhibition of Cholesterol Absorption Homan R, Krause BR Ref: Curr.Pharma.Design, 3:29, 1997 : PubMed
The growing evidence linking elevated plasma cholesterol levels, to increased risk of heart disease and the demonstration of a positive correelation between plasma levels of low density lipoprotein cholesterol and cholesterol absorption efficiency in humans have been a major impetus for efforts to develo cholesterol absorption inhibitors. Not only do such agents act on a major component of the total cholesterol turnover within the body, but, since they are directed at a cholesterol pool that is external to the circulation (i.e. intestinal lumen), there is potential Fot the development of efficacious compounds that function non-systemically and thereby avoid the toxicity issues associated with agents that must enter the circulation to act. The potential for such agents is already evident from the clinical experience with neomycin and beta-sitosterol which have yielded moderate success in the treatment of hypcrcholestetolemic patients. The creation of more efficacious compounds is focused on the development of inhibitors of specific enzymes considered to facilitate the cholesterol absorption process and on non-specific agents that enhance cholesterol retention within the intestinal contents by perturbing cholesterol distribution and exchange among the various lipid phases of the contents. In addition, a new method for blocking cholesterol uptake is proprosed that is based on ihe inhibition of pancreatic phospholipase A2
