Destruction and reformation of an iron-sulfur cluster during catalysis by lipoyl synthase

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Science  20 Oct 2017:
Vol. 358, Issue 6361, pp. 373-377
DOI: 10.1126/science.aan4574

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Refueling an enzyme

Lipoic acid is an eight-carbon fatty acid in which sulfur groups are appended on two carbon atoms by the enzyme lipoyl synthase (LipA). LipA provides the sulfurs from an auxiliary [4Fe-4S] cluster. McCarthy and Booker show that in Escherichia coli, the auxiliary LipA cluster is reconstituted by the iron-sulfur cluster carrier protein NfuA (see the Perspective by Rosenzweig). This occurs fast enough that LipA can act catalytically in the final step of lipoic acid biosynthesis.

Science, this issue p. 373; see also p. 307


Lipoyl synthase (LipA) catalyzes the last step in the biosynthesis of the lipoyl cofactor, which is the attachment of two sulfhydryl groups to C6 and C8 of a pendant octanoyl chain. The appended sulfur atoms derive from an auxiliary [4Fe-4S] cluster on the protein that is degraded during turnover, limiting LipA to one turnover in vitro. We found that the Escherichia coli iron-sulfur (Fe-S) cluster carrier protein NfuA efficiently reconstitutes the auxiliary cluster during LipA catalysis in a step that is not rate-limiting. We also found evidence for a second pathway for cluster regeneration involving the E. coli protein IscU. These results show that enzymes that degrade their Fe-S clusters as a sulfur source can nonetheless act catalytically. Our results also explain why patients with NFU1 gene deletions exhibit phenotypes that are indicative of lipoyl cofactor deficiencies.

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