Session: Undergraduate Research at the Frontiers of Inorganic Chemistry:

Enzymes known as Acireductone Dioxygenases (ARDs) are directly linked to the production of polyamines through their role in the methionine salvage pathway (MSP). Polyamines contribute to cell growth, cell proliferation, and cell survival in the body, so these functions are regulated via ARD and the MSP. Acireductone Dioxygenases are a family of enzymes that demonstrate different chemical and physical properties depending on the metal that is bound in the active site. If iron (Fe2+) is bound to the active site, ARD will perform the penultimate step in the MSP and ultimately produce polyamines. However if nickel (Ni2+) is bound to the active site, ARD will perform an off-pathway reaction leading to the production of carbon monoxide. In the off-pathway reaction, no polyamines are produced. The distinctive production of carbon monoxide makes ARD’s off-pathway reaction a novel source of CO in the cell, and only the second confirmed source of endogenous CO. The purpose for the production of CO as well as the role of the off-pathway reaction must be explored due to ARD’s association with disease. Studies showed that ARD was either upregulated or downregulated in patients with different types of cancers, which gives reason to believe that ARD and cancer may be linked. For example, upregulation of both the on-pathway and off-pathway reaction would lead to an excess of either polyamines or CO, which both could contribute to the production of tumors in the body. Few functional models of ARD have been synthesized in order to study aspects of how ARD functions mechanistically. Although these are functional models, all ARD model complexes synthesized to this date have chelating ligands with an N3, N4 or N4O coordination motif, and these do not accurately model the electronic structure of the enzyme’s active site (His3-Glu1 coordination motif). Following up on our most recent family of model complexes, we introduce the synthesis and characterization of a second generation of ARD models with N3O pyridine, phenolate based ligands. Their preliminary biomimetic reactivity and computational studies for these complexes will be discussed. These complexes and their flexible coordination motif as well as possible metal mediated O2 activation have direct implications for how these factors might influence the off-pathway reactivity in ARD.

Thomas Cundari

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