Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are two unique heme-containing metalloenzymes that catalyze the oxidative cleavage of the indole ring in essential, and energetically-expensive amino acid tryptophan during the first and rate-limiting event of the kynurenine pathway. Moreover, these enzymes have been the focal point of numerous recent studies owing to their implications in multiple pathogenic conditions with paramount significance in human health. Despite the intense research and substantial developments in the field, designing bio-inspired model systems of such enzymes has continued to be a challenging endeavor. Such models could serve as powerful tools in shedding light on some of the yet obscure critical mechanistic details pertaining to TDO and IDO. This work depicts a synthetic heme superoxide-based model system that closely mimic the TDO/IDO (bio)chemistry, where a series of electronically disparate porphyrin-based superoxo complexes is shown to dioxygenate an array of indole substrates that serve as tryptophan models. Despite being classified as sluggish oxidants, these heme superoxide model systems are demonstrated to efficiently oxidize these indole substrates in a dioxygenation fashion, revealing important electronic effects exerted by the heme center. Our studies further reveal the involvement of a ferryl species (Fe<sup>IV</sup>=O) within this mechanism, and present its unequivocal characterization as a reaction intermediate, paralleling similar observations during IDO turnover. Comprehensive insights into the mechanistic events, and relevance and properties of key reaction intermediates involved during TDO/IDO mediated oxygenation will be discussed in detail.<br/>

Modeling tryptophan/indoleamine 2,3-dioxygenase with heme superoxide mimics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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