Acyl coenzyme A: cholesterol

L. L. Gallo, S. B. Clark, S. Myers, G. V. Vahouny, Cholesterol Absorption in Rat Intestine Role of Cholesterol Esterase and Acyl Coenzyme A Cholesterol Acyltransferase , J. Lipid Res. 1984, 25, 604-612. 

T. F. Woolf, A. Black, Y. Y. Shum, W. Mcnally, H. Lee, T. Chang, BioDisposion Studies with the Acyl-Coenzyme-A-Cholesterol Acyltransferase Inhibitor 2,2-Dimethyl-V-(2,4,6-Trimethoxyphenyfidodecanamide, CI-976 , Drug Metab. Dispos. 1993, 21, 1112-1118. 

Puglielli, L., Konopka, G., Pack-Chung, E., Ingano, L.A., Berezovska, O., Hyman, B.T., Chang, T.Y., Tanzi, R.E., and Kovacs, D.M., Acyl-coenzyme A cholesterol acyltransferase modulates the generation of the amyloid beta-peptide, Nat. Cell Biol., 3, 905, 2001. 

Inskeep, P. B., K. M. Davis, and A. E. Ree. Pharmacokinetics of the acyl coenzyme A cholesterol acyl transferase inhibitor CP-105,191 in dogs-the effect of food and sesame oil on systemic exposure following oral dosing. J Pharm Sci 1995 84(2) 131-133. Satchithanandam, S., M. Reicks, R. J. Calvert, M. M. Cassidy, and D. Kritchevsky. Coconut oil and sesame... 

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

P Oelkers, A Behari, D Cromley, JT Billheimer, SL Sturley. Characterization of two human genes encoding acyl coenzyme A cholesterol acyltransferase-related enzymes. J Biol Chem 273 26765-26771, 1998. 

Fig. 3. Steroidogenic pathway in granulosa cells. A. Lipoprotein in receptors. B. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). C. Acyl-coenzyme A (cholesterol acyl transferase). D. Cholesterol esterase. E. Cholesterol transport to the mitochondria. F. Cholesterol side-chain cleavage enzymes (phospholipid membrane environment and enzyme levels). G. 3/3-Hydroxysteroid dehydrogenase (3/3-HSD). H. 20a-Hydroxysteroid dehydrogenase (20a-HSD). I. Aromatases.

Fig. 4. Potential sources of the immediate precursor pool of unesterified cholesterol available for mitochondrial steroidogenesis. ACAT, microsomal acyl coenzyme A cholesterol acyltransferase SEH, sterol ester hydrolase. From Ref. 14.

Rumsey, S. C., Galeano, N., Lipschitz, B., and Deckelbaum, R. J. (1995). Oleate and other long-chain fatty acids stimulate low-density-lipoprotein receptor activity by enhancing acyl coenzyme A cholesterol acyltransferase activity and altering intracellular regulatory cholesterol pools in cultured cells. /. Biol. Chem. 270,10008-100016. 

P. Fehringer, F. Notka, C. Aslanidis, and G. Schmitz, Purification, cloning, and expression of a human enzyme with acyl coenzyme A cholesterol acyltransfer-ase activity, which is identical to liver car-boxylesterase, Arterioscler. Thromh. Vase. Biol., 1994, 34, 1346-1455. 

Endoplasmic reticulum (ER) and Golgi apparatus Inactivation of the ER-specihc enzyme acyl coenzyme A cholesterol-O-acyl transferase extensive swelling decreased synthesis and transport of plasma membrane proteins (which occurs in rough ER and Golgi apparatus)... 

Ezetimibe (Fig. 12.3) is a drug that works by reduction of blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. As indicated above, cholesterol in the body is derived from dietary sources or is synthesised in the body. Acyl Coenzyme A Cholesterol A Transferase (ACAT) is a membrane protein that catalyses the synthesis of cholesteryl esters from cholesterol. Inhibition of ACAT has therefore been... 

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