Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase

Structure-effect relationships and evidence for an allosteric mechanism

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 μM, 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 μM). 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.

Original languageEnglish
Pages (from-to)1557-1566
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1770
Issue number11
DOIs
Publication statusPublished - Nov 1 2007

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Glucuronosyltransferase
Adenine Nucleotides
Hymecromone
Adenine
Adenosine Monophosphate
Nucleotides
NADP
Estradiol
Adenosine Triphosphate
Guanosine Triphosphate
Inhibitory Concentration 50
Rats
Uridine Diphosphate Glucuronic Acid
Allosteric Site
Cytidine Triphosphate
Cytosine
Guanine
Liver Microsomes
Endoplasmic Reticulum
Detergents

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Inhibitory effects of adenine nucleotides and related substances on UDP-glucuronosyltransferase : Structure-effect relationships and evidence for an allosteric mechanism. / Nishimura, Yoshio; Maeda, Shingo; Ikushiro, Shin ichi; Mackenzie, Peter I.; Ishii, Yuji; Yamada, Hideyuki.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1770, No. 11, 01.11.2007, p. 1557-1566.

Research output: Contribution to journalArticle

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