Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism.

Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. Research Abstract Details 

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Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. Abstract Text:

Yoshio Nishimura,Shingo Maeda,Shin-ichi Ikushiro,Peter I Mackenzie,Yuji Ishii,Hideyuki Yamada,Yoshio Nishimura,Shingo Maeda,Shin-ichi Ikushiro,Peter I Mackenzie,Yuji Ishii,Hideyuki Yamada,Yoshio Nishimura,Shingo Maeda,Shin-ichi Ikushiro,Peter I Mackenzie,Yuji Ishii,Hideyuki Yamada,

The inhibitory effects of nucleotides and related substances on rat hepatic UDP-glucuronosyltransferase (UGT) were studied. ATP and NADP+ markedly reduced 4-methylumbelliferone (4-MU) UGT activity only when detergent-treated rat liver microsomes were used as the enzyme source. The IC50 values of adenine, ATP, NAD+ and NADP+ were estimated to be below 20 microM, whereas AMP had no inhibitory effect. From the kinetic behavior observed, these adenine-related compounds were assumed to inhibit UGT activity non-competitively without competing with either 4-MU or UDP-glucuronic acid. Among guanine, cytosine and their related nucleotides, only triphosphate nucleotides (CTP and GTP) exhibited potent UGT inhibition, although the effect of GTP was weak. Estradiol 3- and 17-glucuronidation were also inhibited by the inhibitors of 4-MU UGT. The only exception was that estradiol 17-glucuronidation activity was inhibited by AMP (IC50=31 microM). In addition, AMP antagonized the inhibitory effects of adenine, ATP, and NADP+ on 4-MU and estradiol 3- glucuronidation activities. These results suggest that (1) a number of cellular nucleotides present within the endoplasmic reticulum regulate UGT function; and (2) these substances bind to a common allosteric site on UGT to reduce catalytic function.

Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. Publishing Authors By Initials

Y Nishimura,S Maeda,S Ikushiro,PI Mackenzie,Y Ishii,H Yamada,Y Nishimura,S Maeda,S Ikushiro,PI Mackenzie,Y Ishii,H Yamada,Y Nishimura,S Maeda,S Ikushiro,PI Mackenzie,Y Ishii,H Yamada,

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Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biochimica et biophysica acta

VOLUME: 1770

Page Numbers: 1557-66

Journal Abbreviation: Biochim. Biophys. Acta

ISSN: 0006-3002

DAY: 8

MONTH: 08

YEAR: 2007

Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism. Information

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LANGUAGE: eng

NlmUniqueID: 217513

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Grant and Affiliation Information for Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase: structure-effect relationships and evidence for an allosteric mechanism.

AFFILIATION: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Country: Netherlands

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MEDLINETA: Biochim Biophys Acta

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