Tryptophan catabolism has been recently implicated in a vast variety of critical pathogenic conditions in humans, including cancer. Two heme enzymes catalyze the dioxygenation of tryptophan, namely tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). These enzymes mediate the oxidative cleavage of the 2,3-double bond of the indole ring in tryptophan using dioxygen, producing <i>N</i>-formylkynurenine in the first and rate-limiting step of kynurenine pathway. While being involved in critical physiological functions such as immunoregulation and aging, TDO and IDO are known to aid malignant cells in evading host immunosurveillance by effecting tryptophan degradation in human T-cells. Thus, TDO/IDO inhibitors are actively and rigorously interrogated as potential anti-cancer agents. However, precise mechanistic details pertaining to these pivotal heme enzymes are severely lacking, significantly impeding the rational designing of TDO/IDO inhibitors with enhanced therapeutic potential. This work, for the first time, describes a series of heme superoxide model systems that closely mimic the TDO/IDO (bio)chemistry, where an array of indole substrates is demonstrated to undergo heme superoxide-mediated dioxygenation, where dioxygen is the sole oxidant. Critical, unprecedented close view of the mechanistic details and intermediates is presented, including a putative, biologically relevant ferryl (Fe<sup>IV</sup>=O) intermediate. This study not only marks the first instance where proposed heme superoxide oxidants are demonstrated to mediate indole oxidation chemistry paralleling TDO and IDO, but also reveals the remarkable substrate oxidation capabilities of heme superoxide adducts, warranting reevaluation of their prior classification as sluggish oxidants.

Bio-inspired dioxygenation reactivity landscapes of synthetic heme superoxide adducts

ACS Spring Meeting 2021

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