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The biosynthesis of lipoic acid: a saga of death, destruction, and rebirth

The biosynthesis of lipoic acid: a saga of death, destruction, and rebirth

Air date: Wednesday, May 1, 2019, 3:00:00 PM

Category: WALS – Wednesday Afternoon Lectures

Runtime: 01:02:20

Description: NIH Director’s Wednesday Afternoon Lecture Series

Dr. Booker’s laboratory is endeavoring to understand at the molecular level the reaction mechanisms employed by various enzymes, and then to exploit what is learned to impact favorably on human health. A particular focus is to understand the manner in which enzymes bind and use cofactors—whether simple metal ions, complex metal clusters, or small molecules—to increase their catalytic capabilities beyond that which is supported by the functional groups of the 20 naturally occurring amino acids. His lab is particularly interested in understanding the mechanisms of enzymes that use iron-sulfur clusters and/or S-adenosylmethionine in catalysis.

In his lecture, Dr. Booker will describe the workings of Lipoyl synthase (LipA), a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes. LipA catalyzes the sequential insertion of sulfur atoms at C6 and C8 of an amide-linked octanoyl chain on a lipoyl carrier protein (LCP) to afford the lipoyl cofactor. This cofactor plays key roles in several multienzyme complexes that are involved in energy or amino acid metabolism. LipA contains two essential [4Fe–4S] clusters. One of the clusters interacts with SAM to generate two 5′-deoxyadenosyl 5′-radical intermediates that abstract hydrogen atoms from C6 and C8 of the octanoyl chain, while the second cluster is believed to provide the inserted sulfur atom. Therefore, LipA becomes inactivated upon one full turnover due to destruction of its iron-sulfur (Fe/S) cluster cofactor.

Dr. Booker and his colleagues provide strong evidence for this provocative role for an Fe/S cluster in enzymatic catalysis. When his laboratory conducts reactions under conditions wherein only one sulfur atom is inserted into the organic substrate, the researchers find that the LCP substrate becomes cross-linked to LipA through the Fe/S cluster. Extensive characterization of the cross-linked species by Mossbauer spectroscopy and X-ray crystallography shows that it contains three iron ions and three sulfide ions in a cubane-like structure that is connected to the LCP by a bridging monothiolated octanoyl linker. Upon isolation of the species and its reintroduction into a new reaction mixture, formation of the lipoyl product is observed with kinetics that are consistent with the overall rate of catalysis.

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Author: Squire J. Booker, Ph.D., Howard Hughes Medical Investigator; Evan Pugh University Professor of Chemistry, Professor of Biochemistry and Molecular Biology, Eberly Distinguished Chair in Science, Pennsylvania State University

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B. Moragne
B. Moragne
7 months ago

I'm slightly confused. Is the sulfur present in lets say the body able to complete the biosynthesis of ALA? As in taking it as an Anti-aging compound? Virtually because of the interaction with sulfur?

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