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Peer-reviewedCC BYACS bio & med chem Au

Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid.

  • Olga E Esakova1,2
  • Caitlin D Palmer1
  • Douglas M Warui1,2
  • Erin L McCarthy3
  • Squire J Booker4,1,3,5,2
5 affiliations
  1. 1Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  2. 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States.
  3. 3Department of Biochemistry & Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  4. 4Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  5. 5Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
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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.

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Cite

BibTeXRIS
BibTeX
@article{esakova2026lipoyl,
  title = {{Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid.}},
  author = {Olga E Esakova and Caitlin D Palmer and Douglas M Warui and Erin L McCarthy and Squire J Booker},
  journal = {ACS bio \& med chem Au},
  year = {2026},
  month = jul,
  doi = {10.1021/acsbiomedchemau.6c00104},
  url = {https://europepmc.org/article/MED/42921321},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid.
AU  - Olga E Esakova
AU  - Caitlin D Palmer
AU  - Douglas M Warui
AU  - Erin L McCarthy
AU  - Squire J Booker
PY  - 2026
DA  - 2026/07/25
JO  - ACS bio & med chem Au
DO  - 10.1021/acsbiomedchemau.6c00104
UR  - https://europepmc.org/article/MED/42921321
AB  - 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.
SN  - 2694-2437
ER  -