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J. Biol. Chem., Vol. 278, Issue 23, 20526-20532, June 6, 2003

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Mismatch Uracil Glycosylase from Escherichia coli

A GENERAL MISMATCH OR A SPECIFIC DNA GLYCOSYLASE?^*

Rory J. O'Neill , Olga V. Vorob'eva , Hassan Shahbakhti , Erik Zmuda ¶, Ashok S. Bhagwat  and Geoffrey S. Baldwin  ||

From the Imperial College London, Department of Biological Sciences, Sir Alexander Flemming Building, South Kensington, London SW7 2AZ, United Kingdom, the 463 Chemistry Building, Department of Chemistry, Wayne State University, Detroit, Michigan 48202-3489, and ^¶Trevigen, Gaithersburg, Maryland 20877

The gene for the mismatch-specific uracil glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the mammalian thymine DNA glycosylase, with activity against uracil in U·G mismatches. Subsequently, 3,N⁴-ethenocytosine (C), thymine, 5-hydroxymethyluracil, and 8-(hydroxymethyl)-3,N⁴-ethenocytosine have been proposed as possible substrates for this enzyme. The evaluation of various DNA adducts as substrates is complicated by the biphasic nature of the kinetics of this enzyme. Our results demonstrate that product release by the enzyme is very slow and hence comparing the "steady-state" parameters of the enzyme for different substrates is of limited use. Consequently, the ability of the enzyme to excise a variety of damage products of purines and pyrimidines was studied under single turnover conditions. Although the enzyme excised both C and U from DNA, the former adduct was significantly better as a substrate in terms of binding and hydrolysis. Some products of oxidative and alkylation damage are also moderately good substrates for the enzyme, but thymine is a poor substrate. This comparison of different substrates under single turnover conditions provides a rational basis for comparing substrates of MUG and we relate these conclusions to the known crystal structures of the enzyme and its catalytic mechanism.

Received for publication, October 23, 2002 , and in revised form, March 27, 2003.

^* This work was supported by the Biotechnology and Biological Sciences Research Council (UK) and the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 44-20-7594-5288; Fax: 44-20-7584-2056; E-mail: g.baldwin{at}ic.ac.uk.

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