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Chemical synthesis of bile acid acyl-adenylates and formation by a rat liver microsomal fraction
Authors:Shigeo Ikegawa  Hiromi Ito  Masako Maeda  Kuniko Mitamura
Institution:a Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-osaka, 577-8502, Japan
b School of Pharmaceutical Sciences, Showa University, 1-5-8, Hatanodai, Shinagawa, Tokyo, 142-8555, Japan
c Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0063, United States
Abstract:In mammals, unconjugated bile acids formed in the intestine by bacterial deconjugation are reconjugated (N-acylamidated) with taurine or glycine during hepatocyte transport. Activation of the carboxyl group of bile acids to form acyl-adenylates is a likely key intermediate step in bile acid N-acylamidation. To gain more insight into the process of bile acid adenylate formation, we first synthesized the adenylates of five common, natural bile acids (cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, and lithocholic acid), and confirmed their structure by proton NMR. We then investigated adenylate formation by subcellular fractions of rat liver (microsomes, mitochondria, cytosol) using a newly developed LC method for quantifying adenylate formation. The highest activity was observed in the microsomal fraction. The reaction required Mg2+ and its optimum pH was about pH 7.0. In term of maximum velocity (Vmax) and the Michaelis constant (Km), the catalytic efficiency of the enzyme under the conditions used was highest with cholic acid of the bile acids tested. The formation of cholyl-adenylate was strongly inhibited by lithocholic and deoxycholic acid, as well as by palmitic acid; ibuprofen and valproic acid were weak inhibitors. In cholestatic disease, such adenylate formation might lead to subsequent bile acid conjugation with glutathione or proteins.
Keywords:Cholyl-adenylate (CA-AMP)  cholyl adenosine 5&prime  -phosphate diester  Deoxycholyl-adenylate (DCA-AMP)  deoxycholyl adenosine 5&prime  -phosphate diester  Ursodeoxycholyl-adenylate (UDCA-AMP)  ursodeoxycholyl adenosine 5&prime  -phosphate diester  Lithocholyl-adenylate (LCA-AMP)  lithocholyl adenosine 5&prime  -phosphate diester  12-Oxolithocholyl-adenylate (12-oxoLCA-AMP)  12-oxolithocholyl adenosine 5&prime  -phosphate diester  Valproyl-adenylate (valproyl-AMP)  valproyl adenosine 5&prime  -phosphate diester  Ibuprofenyl-adenylate (ibuprofenyl-AMP)  ibuprofenyl adenosine 5&prime  -phosphate diester  AMP  adenosine 5&prime  -monophosphate  ATP  adenosine-5&prime  -triphosphate  Palmitic acid  hexadecanoic acid  Valproic acid  2-propylpentanoic acid  Ibuprofen  2-[4-(2-methylpropyl)phenyl]propanoic acid
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