Erin McCarthy, a recent graduate of Penn State’s Biochemistry, Microbiology, and Molecular Biology Graduate Program (BMMB), has been honored with the 2020 Fred Wedler Outstanding Doctoral Dissertation Award.
Each year, the Department of Biochemistry and Molecular Biology, selects one doctoral student to receive the award. It is given to the student whose dissertation is judged to be the best, based on evaluation criteria given to the student’s dissertation committee. Each student defending a doctoral dissertation is automatically considered for the award.
Erin’s dissertation sought to understand a fundamental question within the field of enzymology – how are proteins that destroy their metallocofactors during their reaction mechanism are regenerated to support catalysis? The hallmark of her research was the discovery of a novel protein factor that efficiently restored the auxiliary Fe-S (iron-sulfur) cluster of lipoyl synthase (LipA) to support turnover in the production of lipoic acid, an essential molecule in the body. LipA destroys its auxiliary Fe-S cluster to use as a source of sulfur in the reaction. This leaves LipA in an inactive state due to the absence of a system for its regeneration to support another round of product formation. Erin’s research found that a second Fe-S cluster containing protein, NfuA, can target LipA activating it for additional reactions.
Erin’s research has shown that E. coli NfuA, a [4Fe–4S] cluster carrier protein, can regenerate the cluster on LipA at a rate that does not impede catalysis. Her results show, for the first time, that enzymes that degrade their Fe-S clusters as a sulfur source are not simply substrates, but true catalysts. With several clinical diseases associated with defects in iron-sulfur cluster assembly and trafficking, as well as with lipoic acid deficiency, Erin’s work explains why patients with mutations in the gene encoding for the human homolog, NFU1, have been diagnosed with fatal diseases associated with lipoic acid deficiency.
Erin’s work has shed light on many important biological questions, such as how the lipoyl cofactor is biosynthesized in the cell, the mechanism by which enzymes catalyze the attachment of sulfur to an inactivated carbon center, and the mechanism by which newly assembled Fe-S clusters are targeted and subsequently transferred to proteins that use these metal cofactors for catalysis. In the end, her research not only shows that LipA is capable of enzyme catalysis, but also provides insight for some clinical conditions associated with lipoic acid deficiency.
Erin defended her thesis and earned her Ph.D. from the BMMB Program in 2020. While a student she worked, and studied, under the guidance of Evan Pugh University Professor of Chemistry and of Biochemistry and Molecular Biology, Squire Booker. Currently, she lives in Cranford, New Jersey, and is employed as a Senior Scientist at Merck.