Lipoyl  synthase, LipA, is a RS enzyme that catalyzes the second step of the de novo biosynthesis of lipoic acid, an essential cofactor known for its prominent roles in energy metabolism and degradation of certain amino acids. In addition to the radical SAM [4Fe–4S] cluster, Iipoyl synthase coordinates a second ‘auxiliary’ [4Fe–4S] cluster that has been shown to be sacrificed as a sulfur source during catalysis, leaving LipA in an inactive state in the absence of a system to regenerate it. Recently, we have provided evidence that E. coli NfuA, an Fe–S cluster-containing protein suggested to serve as an intermediate in Fe–S cluster delivery, restores E. coli LipA for subsequent turnover in a non-rate limiting step. Efforts to elucidate the mechanistic details of the regeneration of E. coli LipA’s auxiliary cluster are ongoing.

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