dc.creatorCapece, Luciana
dc.creatorLewis-Ballester, Ariel
dc.creatorMarti, Marcelo Adrian
dc.creatorEstrin, Dario Ariel
dc.creatorYeh, Syun-Ru
dc.date.accessioned2019-01-28T15:01:35Z
dc.date.accessioned2022-10-14T23:12:48Z
dc.date.available2019-01-28T15:01:35Z
dc.date.available2022-10-14T23:12:48Z
dc.date.created2019-01-28T15:01:35Z
dc.date.issued2011-11-23
dc.identifierCapece, Luciana; Lewis-Ballester, Ariel; Marti, Marcelo Adrian; Estrin, Dario Ariel; Yeh, Syun-Ru; Molecular basis for the substrate stereoselectivity in tryptophan dioxygenase; American Chemical Society; Biochemistry; 50; 50; 23-11-2011; 10910-10918
dc.identifier0006-2960
dc.identifierhttp://hdl.handle.net/11336/68712
dc.identifierCONICET Digital
dc.identifierCONICET
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/4318031
dc.description.abstractTryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are the only two heme proteins that catalyze the oxidation reaction of tryptophan (Trp) to Nformylkynurenine.<br />While human IDO is able to oxidize both Land 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 NH3+ 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,<br />loop250−260 and loop117−130, critical for substrate binding.
dc.languageeng
dc.publisherAmerican Chemical Society
dc.relationinfo:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/abs/10.1021/bi201439m
dc.relationinfo:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/bi201439m
dc.relationinfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237892/
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectIndeolamine Dioxygenase
dc.subjectTryptophane Dioxygenase
dc.subjectComputer Simulation
dc.titleMolecular basis for the substrate stereoselectivity in tryptophan dioxygenase
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:ar-repo/semantics/artículo
dc.typeinfo:eu-repo/semantics/publishedVersion


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