Human iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) dioxygenases catalyze hydroxylation of inactivated aliphatic carbon centers in reactions that are fundamentally important to central life processes (e.g., metabolism and its regulation, transcription, epigenetic inheritance) and relevant to several diseases. Plant, fungi, and bacteria have diversified the Fe/2OG structural and functional platform, using it for a bewildering array of oxidative transformations that include halogenations, dehydrogenations, cyclizations and stereoinversions of aliphatic carbon centers. As the biosynthetic machinery generating a large number of important natural-product drugs are replete with such Fe/2OG oxygenases, a predictive understanding of the reaction mechanisms and how the individual enzymes direct them could enable re-purposing of the enzymes and pathways for tailor-made drug compounds. Having recently made great progress toward understanding the hydroxylation, halogenation, and stereoinversion outcomes, we turn in this project to two of the least well- understood reaction types mediated by members of this enzyme family: oxacycle-installing 1,3- and 1,5- dehydrogenation (oxacyclization) and olefin-installing 1,2-dehydrogenation (desaturation) reactions on the pathways to the antibiotics clavulanic acid and napthyridomycin, the anesthetic scopolamine, and insecticide, norloline. We will elucidate the structures and mechanisms of the enzymes catalyzing these enigmatic reactions to develop an integrated understanding of the chemistry of this important enzyme family.
Iron- and 2-(oxo)glutarate-dependent oxygenase enzymes from plants, fungi, and soil bacteria carry out a bewildering array of oxidative transformations in biochemical pathways to many important natural-product drugs. Most of the reactions are not in the repertoire of synthetic chemists. The precise and predictive understanding of how these enzymes promote their varied outcomes sought in this project would enable rational repurposing of these enzymes and pathways to make new drug compounds with new and improved bioactivities.
| Dunham, Noah P; Chang, Wei-Chen; Mitchell, Andrew J et al. (2018) Two Distinct Mechanisms for C-C Desaturation by Iron(II)- and 2-(Oxo)glutarate-Dependent Oxygenases: Importance of ?-Heteroatom Assistance. J Am Chem Soc 140:7116-7126 |
| Pan, Juan; Bhardwaj, Minakshi; Zhang, Bo et al. (2018) Installation of the Ether Bridge of Lolines by the Iron- and 2-Oxoglutarate-Dependent Oxygenase, LolO: Regio- and Stereochemistry of Sequential Hydroxylation and Oxacyclization Reactions. Biochemistry 57:2074-2083 |
| Mitchell, Andrew J; Dunham, Noah P; Martinie, Ryan J et al. (2017) Visualizing the Reaction Cycle in an Iron(II)- and 2-(Oxo)-glutarate-Dependent Hydroxylase. J Am Chem Soc 139:13830-13836 |
