title: Density functional theory study on a missing piece in understanding of heme chemistry: the reaction mechanism for indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
abstract: Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme-containing dioxygenases and catalyze oxidative cleavage of the pyrrole ring of L-tryptophan. On the basis of three recent crystal structures of these heme-containing dioxygenases, two new mechanistic pathways were proposed by several groups. Both pathways start with electrophilic addition of the Fe(II)-bound dioxygen concerted with proton transfer (oxygen ene-type reaction), followed by either formation of a dioxetane intermediate or Criegee-type rearrangement. However, density functional theory (DFT) calculations do not support the proposed concerted oxygen ene-type and Criegee-type rearrangement pathways. On the basis of DFT calculations, we propose a new mechanism for dioxygen activation in these heme systems. The mechanism involves (a) direct electrophilic addition of the Fe(II)-bound oxygen to the C2 or C3 position of the indole in a closed-shell singlet state or (b) direct radical addition of the Fe(III)-superoxide to the C2 position of the indole in a triplet (or open-shell singlet) state. Then, a radical-recombination or nearly barrierless charge-recombination step from the resultant diradical or zwitterionic intermediates, respectively, proceeds to afford metastable dioxetane intermediates, followed by ring-opening of the dioxetanes. Alternatively, homolytic O-O bond cleavage from the diradical intermediate followed by oxo attack and facile C2-C3 bond cleavage could compete with the dioxetane formation pathway. Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied.
authors: Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan.
authors: Lung Wa
authors: LW
authors: Chung
authors: Xin
authors: X
authors: Li
authors: Hiroshi
authors: H
authors: Sugimoto
authors: Yoshitsugu
authors: Y
authors: Shiro
authors: Keiji
authors: K
authors: Morokuma
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D005559:Formamides / Q000737:chemistry; D006420:Hemeproteins / Q000737:chemistry* / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000737:chemistry* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry; D013816:Thermodynamics; D014366:Tryptophan Oxygenase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000098:Acetophenones; D004852:Epoxy Compounds; D005559:Formamides; D006420:Hemeproteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D008024:Ligands; D011166:Porphyrins; D006859:Hydrogen; D014366:Tryptophan Oxygenase; D010100:Oxygen