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Caught in the Act: Snapshots of Sulfur Insertion by Lipoyl Synthase
Author(s) -
McLaughlin Martin,
Lanz Nicholas,
Goldman Peter,
Lee Kyung Hoon,
Booker Squire,
Drennan Catherine
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.895.4
Subject(s) - chemistry , cofactor , stereochemistry , sulfur , biosynthesis , atp synthase , enzyme , iron–sulfur cluster , methionine , lipoic acid , biochemistry , sulfur metabolism , amino acid , organic chemistry , antioxidant
Lipoic acid, in the form of lipoylated proteins, is critical to aerobic metabolism as a cofactor in various 2‐oxoacid dehydrogenase complexes. 1 Lipoyl synthase (LipA) catalyzes the last step in the formation of the lipoyl cofactor, using two [4Fe‐4S] clusters to successively insert two sulfur atoms at the unactivated C6 and C8 positions of a protein‐bound octanoyl group. 2,3,4 A member of the burgeoning S ‐adenosyl‐L‐methionine (AdoMet) radical superfamily of enzymes, LipA uses one of its [4Fe‐4S] clusters and AdoMet to produce the 5′‐deoxyadenosyl radical, which abstracts a hydrogen atom from substrate before each sulfur insertion. 4,5 Subsequent steps of the reaction are less well understood. Booker et al. have put forth a “cannibalistic” proposal in which the second [4Fe‐4S] cluster serves as sulfur source for the reaction, limiting LipA to one turnover in vitro . 6 We use X‐ray crystallography in combination with biochemical and spectroscopic data to investigate the structure of an active lipoyl synthase and its implications for the mechanism of lipoyl cofactor biosynthesis.