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The biosynthesis of lipoic acid: A saga of death, destruction, and rebirth
Author(s) -
Booker Squire
Publication year - 2022
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.2022.36.s1.0i186
Subject(s) - chemistry , cofactor , sulfur , biosynthesis , stereochemistry , lipoic acid , enzyme , amide , residue (chemistry) , lysine , biochemistry , limiting , amino acid , organic chemistry , antioxidant , mechanical engineering , engineering
Lipoyl synthase (LipA) catalyzes the terminal step in the biosynthesis of the lipoyl cofactor, which is the attachment of sulfur atoms at C6 and C8 of an n ‐octanoyl chain connected in an amide linkage to a specific lysine residue on a lipoyl carrying protein. The protein belongs to the radical S‐adenosylmethionine (SAM) superfamily of enzymes, which use a [4Fe–4S] cluster cofactor to catalyze a reductive cleavage of SAM to generate a 5’‐deoxyadenosyl 5’‐radical (5’‐dA•). The 5’‐dA• removes the C6 and C8 hydrogen atoms for subsequent sulfur attachment; however, the identity of the immediate sulfur source has been controversial. LipA contains a second [4Fe–4S] cluster, which has been proposed to provide the sulfur atoms during the reaction, limiting the enzyme just to one turnover due to destruction of a required cofactor. In this lecture, biochemical, spectroscopic, and structural evidence for this unique sacrificial role in catalysis will be provided. Moreover, evidence that the cluster can be reconstructed after each turnover will be presented.