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Different Mechanisms of Catalytic Complex Formation in Two L-Tryptophan Processing Dioxygenases

Nienhaus, Karin; Nienhaus, G. Ulrich

Abstract:
The human heme enzymes tryptophan 2,3-dioxygenase (hTDO) and indoleamine 2,3 dioxygenase (hIDO) catalyze the initial step in L-tryptophan (L-Trp) catabolism, the insertion of dioxygen into L-Trp. Overexpression of these enzymes causes depletion of L-Trp and accumulation of metabolic products, and thereby contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. Understanding the assembly of the catalytically active, ternary enzyme-substrate-ligand complexes is not yet fully resolved, but an essential prerequisite for designing efficient and selective de novo inhibitors. Evidence is mounting that the ternary complex forms by sequential binding of ligand and substrate in a specific order. In hTDO, the apolar L-Trp binds first, decreasing active-site solvation and, as a result, reducing non-productive oxidation of the heme iron by the dioxygen ligand, which may leave the substrate bound to a ferric heme iron. In hIDO, by contrast, dioxygen must first coordinate to the heme iron because a bound substrate would occlude ligand access to the heme iron, so the ternary complex can no longer form. Consequently, faster association of L-Trp at high concentrations results in substrate inhibition. ... mehr

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Verlagsausgabe §
DOI: 10.5445/IR/1000089040
Veröffentlicht am 04.01.2019
Originalveröffentlichung
DOI: 10.3389/fmolb.2017.00094
Scopus
Zitationen: 3
Coverbild
Zugehörige Institution(en) am KIT Institut für Angewandte Physik (APH)
Institut für Nanotechnologie (INT)
Publikationstyp Zeitschriftenaufsatz
Jahr 2018
Sprache Englisch
Identifikator ISSN: 2296-889X
urn:nbn:de:swb:90-890407
KITopen-ID: 1000089040
HGF-Programm 43.23.01 (POF III, LK 01)
Erschienen in Frontiers in molecular biosciences
Band 4
Seiten Article: 94
Bemerkung zur Veröffentlichung Gefördert durch den KIT-Publikationsfonds
Vorab online veröffentlicht am 04.01.2018
Schlagworte indoleamine 2, 3-dioxygenase; tryptophan dioxygenase; flash photolysis; self-inhibition; ternary complex formation; active-site hydration
Nachgewiesen in Scopus
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