title: Assembly of Lipoic Acid on Its Cognate Enzymes: an Extraordinary and Essential Biosynthetic Pathway.
abstract: Although the structure of lipoic acid and its role in bacterial metabolism were clear over 50 years ago, it is only in the past decade that the pathways of biosynthesis of this universally conserved cofactor have become understood. Unlike most cofactors, lipoic acid must be covalently bound to its cognate enzyme proteins (the 2-oxoacid dehydrogenases and the glycine cleavage system) in order to function in central metabolism. Indeed, the cofactor is assembled on its cognate proteins rather than being assembled and subsequently attached as in the typical pathway, like that of biotin attachment. The first lipoate biosynthetic pathway determined was that of Escherichia coli, which utilizes two enzymes to form the active lipoylated protein from a fatty acid biosynthetic intermediate. Recently, a more complex pathway requiring four proteins was discovered in Bacillus subtilis, which is probably an evolutionary relic. This pathway requires the H protein of the glycine cleavage system of single-carbon metabolism to form active (lipoyl) 2-oxoacid dehydrogenases. The bacterial pathways inform the lipoate pathways of eukaryotic organisms. Plants use the E. coli pathway, whereas mammals and fungi probably use the B. subtilis pathway. The lipoate metabolism enzymes (except those of sulfur insertion) are members of PFAM family PF03099 (the cofactor transferase family). Although these enzymes share some sequence similarity, they catalyze three markedly distinct enzyme reactions, making the usual assignment of function based on alignments prone to frequent mistaken annotations. This state of affairs has possibly clouded the interpretation of one of the disorders of human lipoate metabolism.
authors.affiliation: Departments of Microbiology and Biochemistry, University of Illinois, Urbana, Illinois, USA j-cronan@life.uiuc.edu.
authors.forename: John E
authors.initials: JE
authors.lastname: Cronan
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D053898:Biosynthetic Pathways; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D008063:Thioctic Acid / Q000378:metabolism*; D014166:Transferases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D009097:Multienzyme Complexes; C064525:glycine cleavage system; D008063:Thioctic Acid; D000594:Amino Acid Oxidoreductases; D014166:Transferases