Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid
Year: 2026
Type: review
Abstract: Lipoic acid (1,2-dithiolane-3-pentanoic acid or 6,8-thioctic acid) is a sulfur-containing cofactor essential for central metabolism, where it functions in oxidative decarboxylation reactions catalyzed by the 2-oxoacid dehydrogenase complexes and glycine degradation catalyzed by the glycine cleavage system. Beyond its canonical metabolic roles, the redox-active disulfide/dithiol pair of lipoic acid has attracted considerable interest because of its proposed therapeutic relevance in ailments associated with oxidative stress and inflammation, such as Alzheimer’s and Parkinson’s disease. Despite the broad biological importance of this cofactor, the molecular details of its biosynthesis remained elusive for many years because of the unusual chemistry required for sulfur insertion into unactivated carbon centers. Recent advances have subsequently expanded the understanding of this pathway, particularly through mechanistic and structural studies of lipoyl synthase, a radical S-adenosylmethionine enzyme that catalyzes sulfur incorporation during cofactor assembly. This perspective highlights current insights into lipoic acid biosynthesis and lipoyl synthase, with an emphasis on emerging mechanistic paradigms, lipoyl synthase auxiliary cluster function and regeneration, and the broader biochemical context of radical-mediated sulfur insertion.
Source: ACS Bio & Med Chem Au
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
OpenAlex ID: W7171389137