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J. Biol. Chem., Vol. 278, Issue 50, 50091-50100, December 12, 2003

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Catalysis, Stereochemistry, and Inhibition of Ureidoglycolate Lyase^*

Jane K. McIninch, James D. McIninch, and Sheldon W. May

From the School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400

Ureidoglycolate lyase (UGL, EC 4.3.2.3) catalyzes the breakdown of ureidoglycolate to glyoxylate and urea, which is the final step in the catabolic pathway leading from purines to urea. Although the sequence of enzymatic steps was worked out nearly 40 years ago, the stereochemistry of the uric acid degradation pathway and the catalytic properties of UGL have remained very poorly described. We now report the first direct investigation of the absolute stereochemistry of UGL catalysis. Using chiral chromatographic analyses with substrate enantiomers, we demonstrate that UGL catalysis is stereospecific for substrates with the (S)-hydroxyglycine configuration. The first potent competitive inhibitors for UGL are reported here. These inhibitors are compounds which contain a 2,4-dioxocarboxylate moiety, designed to mimic transient species produced during lyase catalysis. The most potent inhibitor, 2,4-dioxo-4-phenylbutanoic acid, exhibits a K_I value of 2.2 nM and is therefore among the most potent competitive inhibitors ever reported for a lyase enzyme. New synthetic alternate substrates for UGL, which are acyl--hydroxyglycine compounds, are described. Based on these alternate substrates, we introduce the first assay method for monitoring UGL activity directly. Finally, we report the first putative primary nucleotide and derived peptide sequence for UGL. This sequence exhibits a high level of similarity to the fumarylacetoacetate hydrolase family of proteins. Close mechanistic similarities can be visualized between the chemistries of ureidoglycolate lyase and fumarylacetoacetate hydrolase catalysis.

Received for publication, April 11, 2003 , and in revised form, September 5, 2003.

^* This work was supported by National Institutes of Health Grant GM40540. 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.

Received partial support from a Molecular Design Institute fellowship.

To whom correspondence should be addressed: School of Chemistry and Biochemistry, Georgia Inst. of Technology, Atlanta, GA 30332-0400. Tel.: 404-894-4052; Fax: 404-894-2295; E-mail: sheldon.may{at}chemistry.gatech.edu.

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