Human Tryptophan Dioxygenase: A Comparison to Indoleamine 2,3-Dioxygenase
- 21 November 2007
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 129 (50), 15690-15701
- https://doi.org/10.1021/ja076186k
Abstract
In contrast to the diverse superfamily of monooxygenases, there are only two classes of heme-containing dioxygenases in humans. One is tryptophan 2,3 dioxygenase (hTDO), and the other is indoleamine 2,3-dioxygenase (hIDO), both of which catalyze the oxidative degradation of Trp to N-formyl kynurenine. Although hTDO and hIDO catalyze the same reaction, they engage in distinct physiological functions. The molecular properties of hTDO, unlike hIDO, have never been explored in the past. Here, we report the first structural and functional characterization of hTDO with resonance Raman and optical absorption spectroscopies. We show that the proximal Fe-His stretching frequency of hTDO is 229 cm-1, 7 cm-1 lower than that of hIDO, indicating its weaker imidazolate character as compared to hIDO. In the CO derivative of the l-Trp-bound enzyme, the Fe−CO stretching and C−O stretching frequencies are 488 and 1972 cm-1, respectively, suggesting that l-Trp binds to the distal pocket with its C2−C3 double bond facing the heme-bound ligand, in contrast to hIDO, in which the indole NH group forms an H-bond with the heme-bound ligand. Moreover, the Km values of hTDO for d-Trp and l-Trp are similar, but the kcat value for d-Trp is 10-fold lower than that for l-Trp. In contrast, in hIDO, the Km value for d-Trp is 700-fold higher than l-Trp, whereas the kcat values are comparable for the two stereoisomers. Taken together, the data indicate that the initial deprotonation reaction of the indole NH group in hTDO is carried out by the evolutionarily conserved distal His, whereas that in hIDO is performed by the heme-bound dioxygen; in addition, the stereospecificity of hTDO is determined by the efficiency of the dioxygen chemistry, whereas that in hIDO is controlled by the substrate affinity.Keywords
This publication has 38 references indexed in Scilit:
- Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenaseProceedings of the National Academy of Sciences, 2007
- Structure−Activity Study of Brassinin Derivatives as Indoleamine 2,3-Dioxygenase InhibitorsJournal of Medicinal Chemistry, 2005
- Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated l-tryptophan metabolismBiochemical and Biophysical Research Communications, 2005
- CO as a vibrational probe of heme protein active sitesJournal of Inorganic Biochemistry, 2005
- Structural and functional properties of hemoglobins from unicellular organisms as revealed by resonance Raman spectroscopyJournal of Inorganic Biochemistry, 2005
- Determinants of the FeXO (X = C, N, O) Vibrational Frequencies in Heme Adducts from Experiment and Density Functional TheoryJournal of the American Chemical Society, 1999
- Resonance Raman Investigation of Fe−N−O Structure of Nitrosylheme in Myoglobin and Its MutantsThe Journal of Physical Chemistry B, 1999
- Heme-Containing OxygenasesChemical Reviews, 1996
- Spin State and Axial Ligand Bonding in the Hydroxide Complexes of Metmyoglobin, Methemoglobin, and Horseradish Peroxidase at Room and Low TemperaturesBiochemistry, 1994
- Studien über den intermediären Stoffwechsel des Tryptophans XVIII—XXIV.Hoppe-Seyler´s Zeitschrift Für Physiologische Chemie, 1936