Influence of 8-substituents on the oxidation of hypoxanthine and 6-thioxopurine by bovine milk xanthine oxidase

Bergmann, Felix; Levene, Lawrence; Govrin, Hanna; Frank, Aryeh

doi:10.1016/0005-2744(77)90318-7

Cited by 10 publications

(2 citation statements)

References 19 publications

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“…must be considered for aqueous solutions of xanthine and many related substrates (4)(5)(6)(7). Since most pyridinium and quinolinium cations exist as unique species in the pH region in which the enzyme is stable (up to approximately pH l l ) , it seemed that such heteroaromatic cations could be profitably used for the detailed exploration of the substrate specificity of this enzyme.…”

Section: Introductionmentioning

confidence: 99%

Specificity of xanthine oxidase for nitrogen heteroaromatic cation substrates

Bunting¹,

Laderoute²,

Norris³

1980

Can. J. Biochem.

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A variety of pyridinium, quinolinium, and benzoquinolinium cations have been investigated as potential substrates for milk xanthine oxidase at pH 9.9 and (or) pH 10.6. Steady-state kinetic parameters (kc, Km and (or) kc/Km) have been evaluated for all substrates which are enzymically oxidized. Simple N-alkyl pyridinium cations are neither substrates nor inhibitors, although N-aryl pyridinium cations are slowly oxidized to the 4-pyridinones. N-Methylpyridinium cations bearing 3-CONH2, 3-CONHCH3, 3-COCH3, 3-CO2- or 3-CN substituents are readily oxidized at C-6 and this suggests an important hydrogen-bonding interaction between an enzyme donor and the C-3 carbonyl substituent. A variety of N-methylquinolinium cations bearing C-6 substituents are enzymically oxidized at C-2. Analogous substituent effects on kc/Km for these 6-substituted 1-methylquinolinium cations and the corresponding 1-(substituted phenyl)-pyridinium cations is suggestive of the relative productive binding orientations of these two classes of substrate in the active site. N-Methylbenzoquinolinium and 1,10-phenanthrolinium cations are the best cationic substrates found to date, and suggest a relatively large active-site region for the reducing substrate, and important hydrophobic interactions between enzyme and substrate. The overall enzymic specificity observed for these cationic substrates allows a mapping of the general features of the reducing substrate binding site of this enzyme.

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Section: Introductionmentioning

confidence: 99%

Specificity of xanthine oxidase for nitrogen heteroaromatic cation substrates

Bunting¹,

Laderoute²,

Norris³

1980

Can. J. Biochem.

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“…Why the pyrazolo ring should result in a difference in V of two orders of magnitude cannot be explained by a geometrical model of the kind proposed here. However an explanation could be attempted following Bergmann et al [40] who have shown that different substituents in the 8 position could modify drastically the V of hydroxylation at position 2, presumably facilitating or impeding the tautomerisation of the purine molecule that these authors postulate is necessary for enzyme substrate binding. Table 2 summarises all the possible complexes formed between the hydroxypurines and the wild type and mutant active sites.…”

Section: The Mutant Enzymementioning

confidence: 99%

A Mutation in the Xanthine Dehydrogenase (Purine Hydroxylase I) of Aspergillus nidulans Resulting in Altered Specificity. Implications for the Geometry of the Active Site

Scazzocchio

Sealy-Lewis

1978

Eur J Biochem

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A point mutation in the structural gene for purine hydroxylase I (xanthine dehydrogenase) of Aspergillus nidulans results in several dramatic pleiotropic effects. The mutant enzyme oxidises 2-hydroxypurine at position 6 rather than 8, shows a 70-fold reduction in the I/ for hypoxanthine, and loses the ability to accept xanthine as a substrate. Allopurinol, a powerful pseudoirreversible inhibitor of the wild type enzyme, behaves as a good substrate of the mutant enzyme. We propose that the substrate and inhibitor specificities of the enzymes depend on the relative position of an orientating site and a catalytic site. All the properties of the mutant enzyme can be explained by assuming that the mutation results in a change of the relative positions of the catalytic and orientating sites.We have assumed that the catalytic site comprises a Mo(V1) atom and an -S-group as proposed by Coughlan [FEBS Lett. 81, 1-9 (1977)l and the orientating site is a lysyl residue. While these assumptions are not strictly necessary for the construction of an abstract geometric model, they are consistent with other data bearing on the structure of the active site of the molybdenum-containing hydroxylases.

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The Reactions and the Structures of Molybdenum Centers in Enzymes

Bray¹

1980

Advances in Enzymology - And Related Areas of Molecular Biology

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Influence of 8-substituents on the oxidation of hypoxanthine and 6-thioxopurine by bovine milk xanthine oxidase

Cited by 10 publications

References 19 publications

Specificity of xanthine oxidase for nitrogen heteroaromatic cation substrates

Specificity of xanthine oxidase for nitrogen heteroaromatic cation substrates

A Mutation in the Xanthine Dehydrogenase (Purine Hydroxylase I) of Aspergillus nidulans Resulting in Altered Specificity. Implications for the Geometry of the Active Site

The Reactions and the Structures of Molybdenum Centers in Enzymes

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