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The Role of Serine 167 in Human Indoleamine 2,3-Dioxygenase: A Comparison with Tryptophan 2,3-Dioxygenase

Chauhan, Nishma and Basran, Jaswir and Efimov, Igor and Svistunenko, Dimitri A and Seward, Harriet E and Moody, Peter CE and Raven, Emma Lloyd (2008) 'The Role of Serine 167 in Human Indoleamine 2,3-Dioxygenase: A Comparison with Tryptophan 2,3-Dioxygenase.' Biochemistry, 47 (16). pp. 4761-4769. ISSN 0006-2960

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The initial step in the L-kynurenine pathway is oxidation of L-tryptophan to N-formylkynurenine and is catalyzed by one of two heme enzymes, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO). Here, we address the role of the conserved active site Ser167 residue in human IDO (S167A and S167H variants), which is replaced with a histidine in other mammalian and bacterial TDO enzymes. Our kinetic and spectroscopic data for S167A indicate that this residue is not essential for O2 or substrate binding, and we propose that hydrogen bond stabilization of the catalytic ferrous-oxy complex involves active site water molecules in IDO. The data for S167H show that the ferrous-oxy complex is dramatically destabilized in this variant, which is similar to the behavior observed in human TDO [Basran et al. (2008) Biochemistry 47, 4752-4760], and that this destabilization essentially destroys catalytic activity. New kinetic data for the wild-type enzyme also identify the ternary [enzyme-O2-substrate] complex. The data reveal significant differences between the IDO and TDO enzymes, and the implications of these results are discussed in terms of our current understanding of IDO and TDO catalysis. © 2008 American Chemical Society.

Item Type: Article
Uncontrolled Keywords: Humans; Cyanides; Ferrous Compounds; Tryptophan Oxygenase; Tryptophan; Serine; Spectrophotometry; Electron Spin Resonance Spectroscopy; Binding Sites; Molecular Structure; Protein Binding; Substrate Specificity; Oxidation-Reduction; Mutation; Catalysis; Hydrogen Bonding; Thermodynamics; Models, Molecular; Indoleamine-Pyrrole 2,3,-Dioxygenase
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 09 Oct 2011 07:36
Last Modified: 15 Jan 2022 00:33

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