Insights into Iron-Sulfur Cluster Delivery and Coordination
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Date
2020-05
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The Ohio State University
Abstract
Metal cofactors are used throughout biology and are vital for life, being involved in nitrogen fixation, cellular metabolism and DNA repair. Iron-sulfur clusters are one of the most ancient and important cofactors necessary for life. Iron-sulfur clusters are first synthesized in the mitochondria in the eukaryotic system and then trafficked to proteins that utilize the iron sulfur cluster in the mitochondria, cytoplasm or nucleus. Lipoic acid synthase (LIAS) is a [4Fe-4S] containing protein that catalyzes the final double sulfur insertion into octanoic acid to synthesize lipoic acid. Lipoic acid is molecule that is used in the pyruvate dehydrogenase complex and the glycine cleavage system. The mechanism of how LIAS obtains its two [4Fe-4S] clusters is not well understood and the specific [2Fe-2S] donor proteins are not well identified. Mutations in LIAS have been known to cause non-ketotichyperglycinemia and infant death. Mutations in potential [2Fe-2S] donors have also shown lowered levels of lipoic acid in patients. A recently discovered [2Fe-2S] protein, mitoNEET, has been under intense investigation due to its very rare and unique 3Cys-1His type coordination. It is hypothesized to have varying roles in the cell, such as protection from reactive oxygen species, [2Fe-2S] donation to apo-acceptor proteins and interactions with a voltage depended anion channel found in the mitochondria. It is the hope of this this work to understand [4Fe-4S] cluster maturation into LIAS and to identify potential physiological donors of a [2Fe-2S] cluster to the enzyme. It also under investigation to determine the importance of the unique coordination site in mitoNEET and to understand how altering this coordination alters the properties of the [2Fe-2S] cluster.
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Keywords
Biochemistry, Inorganic Chemistry, Iron-Sulfur Clusters, Mitochondria, Bioinorganic Chemistry, Enzyme Kinetics