Altered specificity mutations define residues essential for substrate positioning in xanthine dehydrogenase

Annie Glatigny, Peter Hof, Maria J. Romão, Robert Huber, Claudio Scazzocchio

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

We describe the sequence changes of a number of mutations of the Aspergillus nidulans xanthine dehydrogenase (XDH). We have located the amino acids affected by these changes in the three-dimensional (3D) structure of aldehyde oxido-reductase (MOP) from Desulfovibrio gigas, related to eukaryotic XDHs. Of these, two are loss of function mutations, mapping, respectively, in the molybdenum-pterin co-factor (MoCo) domain and in the domain involved in substrate recognition. Changes in two amino acids result in resistance to the irreversible inhibitor allopurinol. In Arg911 two different changes, conserved among all XDHs and MOP but not in other aldehyde oxidases (AO), change the position of hydroxylation of the analogue 2-hydroxypurine from C-8 to C-6. A number of changes affect residues adjacent to the molybdenum or its ligands. Arg911 is positioned in the substrate pocket in a way that it can account for the positioning of purine substrates in relation to the MoCo reactive center, together with a glutamate residue, universally conserved among the XDHs (Glu833).

Original languageEnglish
Pages (from-to)431-438
Number of pages8
JournalJournal of Molecular Biology
Volume278
Issue number2
DOIs
Publication statusPublished - 1 May 1998

Keywords

  • Aspergillus nidulans
  • Molybdoenzymes
  • Substrate binding site

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