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.
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.
Chung
Lung Wa
LW
Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan.
Li
Xin
X
Sugimoto
Hiroshi
H
Shiro
Yoshitsugu
Y
Morokuma
Keiji
K
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
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