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Abstract:

Tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to N-formylkynurenine. While human IDO is able to oxidize both l- and d-Trp, human TDO (hTDO) displays major specificity for l-Trp. In this work, we aim to interrogate the molecular basis for the substrate stereoselectivity of hTDO. Our previous molecular dynamics simulation studies of Xanthomonas campestris TDO (xcTDO) showed that a hydrogen bond between T254 (T342 in hTDO) and the ammonium group of the substrate is present in the l-Trp-bound enzyme, but not in the d-Trp-bound enzyme. The fact that this is the only notable structural alteration induced by the change in the stereo structure of the substrate prompted us to produce and characterize the T342A mutant of hTDO to evaluate the structural role of T342 in controlling the substrate stereoselectivity of the enzyme. The experimental results indicate that the mutation only slightly perturbs the global structural properties of the enzyme but totally abolishes the substrate stereoselectivity. Molecular dynamics simulations of xcTDO show that T254 controls the substrate stereoselectivity of the enzyme by (i) modulating the hydrogen bonding interaction between the NH 3 + group and epoxide oxygen of the ferryl-indole 2,3-epoxide intermediate of the enzyme and (ii) regulating the dynamics of two active site loops, loop 250-260 and loop 117-130, critical for substrate binding. © 2011 American Chemical Society.

Registro:

Documento: Artículo
Título:Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase
Autor:Capece, L.; Lewis-Ballester, A.; Marti, M.A.; Estrin, D.A.; Yeh, S.-R.
Filiación:Departamento de Química Inorgánica, Analítica y Química Física, INQUIMAE-CONICET, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EHA, Argentina
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, United States
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EHA, Argentina
Palabras clave:Active site; Ammonium groups; Dioxygenases; Heme proteins; Hydrogen bonding interactions; Indoleamine 2 ,3-dioxygenase; Molecular basis; Molecular dynamics simulations; Oxidation reactions; Stereostructure; Structural alterations; Substrate binding; Xanthomonas campestris; Amino acids; Ammonium compounds; Dynamics; Enzymes; Hydrogen bonds; Molecular dynamics; Molecular oxygen; Porphyrins; Proteins; Reaction kinetics; Stereoselectivity; Substrates; enzyme; ferryl indole 2,3 epoxide; formylkynurenine; indoleamine 2,3 dioxygenase; tryptophan 2,3 dioxygenase; unclassified drug; article; catalysis; controlled study; enzyme binding; gene mutation; hydrogen bond; molecular dynamics; nonhuman; oxidation; priority journal; protein analysis; protein structure; stereochemistry; Xanthomonas campestris; Amino Acid Substitution; Binding Sites; Biocatalysis; Humans; Hydrogen Bonding; Kinetics; Models, Molecular; Molecular Dynamics Simulation; Mutant Proteins; Oxidation-Reduction; Protein Binding; Protein Conformation; Recombinant Proteins; Spectrophotometry; Spectrum Analysis, Raman; Stereoisomerism; Substrate Specificity; Threonine; Tryptophan; Tryptophan Oxygenase
Año:2011
Volumen:50
Número:50
Página de inicio:10910
Página de fin:10918
DOI: http://dx.doi.org/10.1021/bi201439m
Título revista:Biochemistry
Título revista abreviado:Biochemistry
ISSN:00062960
CODEN:BICHA
CAS:formylkynurenine, 1022-31-7; tryptophan 2,3 dioxygenase, 9014-51-1; Mutant Proteins; Recombinant Proteins; Threonine, 72-19-5; Tryptophan, 73-22-3; Tryptophan Oxygenase, 1.13.11.11
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v50_n50_p10910_Capece

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Citas:

---------- APA ----------
Capece, L., Lewis-Ballester, A., Marti, M.A., Estrin, D.A. & Yeh, S.-R. (2011) . Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase. Biochemistry, 50(50), 10910-10918.
http://dx.doi.org/10.1021/bi201439m
---------- CHICAGO ----------
Capece, L., Lewis-Ballester, A., Marti, M.A., Estrin, D.A., Yeh, S.-R. "Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase" . Biochemistry 50, no. 50 (2011) : 10910-10918.
http://dx.doi.org/10.1021/bi201439m
---------- MLA ----------
Capece, L., Lewis-Ballester, A., Marti, M.A., Estrin, D.A., Yeh, S.-R. "Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase" . Biochemistry, vol. 50, no. 50, 2011, pp. 10910-10918.
http://dx.doi.org/10.1021/bi201439m
---------- VANCOUVER ----------
Capece, L., Lewis-Ballester, A., Marti, M.A., Estrin, D.A., Yeh, S.-R. Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase. Biochemistry. 2011;50(50):10910-10918.
http://dx.doi.org/10.1021/bi201439m