The Role of Serine 167 in Human Indoleamine 2,3-Dioxygenase: A Comparison with Tryptophan 2,3-Dioxygenase
- 28 March 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 47 (16), 4761-4769
- https://doi.org/10.1021/bi702405a
Abstract
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.Keywords
This publication has 14 references indexed in Scilit:
- A Kinetic, Spectroscopic, and Redox Study of Human Tryptophan 2,3-DioxygenaseBiochemistry, 2008
- The Redox Properties of Ascorbate PeroxidaseBiochemistry, 2007
- Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenaseProceedings of the National Academy of Sciences, 2007
- Crystal structure of human indoleamine 2,3-dioxygenase: Catalytic mechanism of O 2 incorporation by a heme-containing dioxygenaseProceedings of the National Academy of Sciences, 2006
- Redox and Spectroscopic Properties of Human Indoleamine 2,3-Dioxygenase and A His303Ala Variant: Implications for CatalysisBiochemistry, 2005
- Structure–Function Relationships of Rat Hepatic Tryptophan 2,3-Dioxygenase: Identification of the Putative Heme-Ligating Histidine ResiduesArchives of Biochemistry and Biophysics, 2001
- Investigation of the haem–nicotinate interaction in leghaemoglobinEuropean Journal of Biochemistry, 2000
- EPR spectroscopy: A powerful technique for the structural and functional investigation of metalloproteinsBiospectroscopy, 1999
- Heme-Containing OxygenasesChemical Reviews, 1996
- Assignment of the axial ligands of ferric ion in low-spin hemoproteins by near-infrared magnetic circular dichroism and electron paramagnetic resonance spectroscopyJournal of the American Chemical Society, 1990