Richard Hall - The Hunt for 8-Oxoguanine Deaminase

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  Hall, Richard S.; Fedorov, Alexander A.; Marti-Arbona, Ricardo;   Fedorov, Elena V.; Kolb, Peter; Sauder, J. Michael; Burley,   Stephen K.; Shoichet, Brian K.; Almo, Steven C.; Raushel, Frank   M..  The Hunt for 8-Oxoguanine Deaminase.  Journal of   the American Chemical Society  (2010), 132(6),   1762-1763.   ISSN: 0002-7863.    DOI:   10.1021/ja909817d.


  An enzyme from Pseudomonas aeruginosa, Pa0142   (gi|9945972), that is able to catalyze the deamination of   8-oxoguanine (8-oxoG) to uric acid has been identified for the   first time. 8-Oxoguanine is formed by the oxidation of guanine   residues within DNA by reactive oxygen species, and this lesion   results in G:C to T:A transversions. The value of   kcat/Km for the   deamination of 8-oxoG by Pa0142 at pH 8.0 and 30 °C is 2.0 ×   104 M−1 s−1. This enzyme can   also catalyze the deamination of isocystosine and guanine at   rates that are approximately an order of magnitude lower. The   three-dimensional structure of a homologous enzyme (gi|44264246)   from the Sargasso Sea has been determined by X-ray diffraction   methods to a resolution of 2.2 Å (PDB entry ). The enzyme folds   as a (β/α)8 barrel and is a member of the   amidohydrolase superfamily with a single zinc in the active site.   This enzyme catalyzes the deamination of 8-oxoG with a   kcat/Km value of 2.7 ×   105 M−1 s−1. Computational   docking of potential high-energy intermediates for the   deamination reaction to the X-ray crystal structure suggests that   active-site binding of 8-oxoG is facilitated by hydrogen-bond   interactions from a conserved glutamine that follows β-strand 1   with the carbonyl group at C6, a conserved tyrosine that follows   β-strand 2 with N7, and a conserved cysteine residue that follows   β-strand 4 with the carbonyl group at C8. A bioinformatic   analysis of available protein sequences suggests that 200 other   bacteria possess an enzyme capable of catalyzing the deamination   of 8-oxoG.

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