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spelling paper:paper_00278424_v106_n41_p17371_LewisBallester2023-06-08T14:54:23Z Evidence for a ferryl intermediate in a heme-based dioxygenase Martí, Marcelo Adrián Capece, Luciana Estrin, Dario Ariel Indoleamine 2,3-dioxygenase Reasonance raman spectroscopy Tryptophan dioxygenase indoleamine 2,3 dioxygenase oxygen tryptophan 2,3 dioxygenase article atom controlled study enzyme chemistry enzyme conformation enzyme mechanism enzyme regulation enzyme structure kinetics priority journal Raman spectrometry Computer Simulation Crystallography, X-Ray Dioxygenases Humans Indoleamine-Pyrrole 2,3,-Dioxygenase Kinetics Kynurenine Spectrum Analysis, Raman Tryptophan In contrast to the wide spectrum of cytochrome P450 monooxygenases, there are only 2 heme-based dioxygenases in humans: tryptophan dioxygenase (hTDO) and indoleamine 2,3-dioxygenase (hIDO). hTDO and hIDO catalyze the same oxidative ring cleavage reaction of L-tryptophan to N-formyl kynurenine, the initial and rate-limiting step of the kynurenine pathway. Despite immense interest, the mechanism by which the 2 enzymes execute the dioxygenase reaction remains elusive. Here, we report experimental evidence for a key ferryl intermediate of hIDO that supports a mechanism in which the 2 atoms of dioxygen are inserted into the substrate via a consecutive 2-step reaction. This finding introduces a paradigm shift in our understanding of the heme-based dioxygenase chemistry, which was previously believed to proceed via simultaneous incorporation of both atoms of dioxygen into the substrate. The ferryl intermediate is not observable during the hTDO reaction, highlighting the structural differences between the 2 dioxygenases, as well as the importance of stereoelectronic factors in modulating the reactions. Fil:Marti, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Capece, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2009 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v106_n41_p17371_LewisBallester http://hdl.handle.net/20.500.12110/paper_00278424_v106_n41_p17371_LewisBallester
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic Indoleamine 2,3-dioxygenase
Reasonance raman spectroscopy
Tryptophan dioxygenase
indoleamine 2,3 dioxygenase
oxygen
tryptophan 2,3 dioxygenase
article
atom
controlled study
enzyme chemistry
enzyme conformation
enzyme mechanism
enzyme regulation
enzyme structure
kinetics
priority journal
Raman spectrometry
Computer Simulation
Crystallography, X-Ray
Dioxygenases
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kinetics
Kynurenine
Spectrum Analysis, Raman
Tryptophan
spellingShingle Indoleamine 2,3-dioxygenase
Reasonance raman spectroscopy
Tryptophan dioxygenase
indoleamine 2,3 dioxygenase
oxygen
tryptophan 2,3 dioxygenase
article
atom
controlled study
enzyme chemistry
enzyme conformation
enzyme mechanism
enzyme regulation
enzyme structure
kinetics
priority journal
Raman spectrometry
Computer Simulation
Crystallography, X-Ray
Dioxygenases
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kinetics
Kynurenine
Spectrum Analysis, Raman
Tryptophan
Martí, Marcelo Adrián
Capece, Luciana
Estrin, Dario Ariel
Evidence for a ferryl intermediate in a heme-based dioxygenase
topic_facet Indoleamine 2,3-dioxygenase
Reasonance raman spectroscopy
Tryptophan dioxygenase
indoleamine 2,3 dioxygenase
oxygen
tryptophan 2,3 dioxygenase
article
atom
controlled study
enzyme chemistry
enzyme conformation
enzyme mechanism
enzyme regulation
enzyme structure
kinetics
priority journal
Raman spectrometry
Computer Simulation
Crystallography, X-Ray
Dioxygenases
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kinetics
Kynurenine
Spectrum Analysis, Raman
Tryptophan
description In contrast to the wide spectrum of cytochrome P450 monooxygenases, there are only 2 heme-based dioxygenases in humans: tryptophan dioxygenase (hTDO) and indoleamine 2,3-dioxygenase (hIDO). hTDO and hIDO catalyze the same oxidative ring cleavage reaction of L-tryptophan to N-formyl kynurenine, the initial and rate-limiting step of the kynurenine pathway. Despite immense interest, the mechanism by which the 2 enzymes execute the dioxygenase reaction remains elusive. Here, we report experimental evidence for a key ferryl intermediate of hIDO that supports a mechanism in which the 2 atoms of dioxygen are inserted into the substrate via a consecutive 2-step reaction. This finding introduces a paradigm shift in our understanding of the heme-based dioxygenase chemistry, which was previously believed to proceed via simultaneous incorporation of both atoms of dioxygen into the substrate. The ferryl intermediate is not observable during the hTDO reaction, highlighting the structural differences between the 2 dioxygenases, as well as the importance of stereoelectronic factors in modulating the reactions.
author Martí, Marcelo Adrián
Capece, Luciana
Estrin, Dario Ariel
author_facet Martí, Marcelo Adrián
Capece, Luciana
Estrin, Dario Ariel
author_sort Martí, Marcelo Adrián
title Evidence for a ferryl intermediate in a heme-based dioxygenase
title_short Evidence for a ferryl intermediate in a heme-based dioxygenase
title_full Evidence for a ferryl intermediate in a heme-based dioxygenase
title_fullStr Evidence for a ferryl intermediate in a heme-based dioxygenase
title_full_unstemmed Evidence for a ferryl intermediate in a heme-based dioxygenase
title_sort evidence for a ferryl intermediate in a heme-based dioxygenase
publishDate 2009
url https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v106_n41_p17371_LewisBallester
http://hdl.handle.net/20.500.12110/paper_00278424_v106_n41_p17371_LewisBallester
work_keys_str_mv AT martimarceloadrian evidenceforaferrylintermediateinahemebaseddioxygenase
AT capeceluciana evidenceforaferrylintermediateinahemebaseddioxygenase
AT estrindarioariel evidenceforaferrylintermediateinahemebaseddioxygenase
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