The classical and proposed lipoic acid biosynthesis pathways. In the proposed pathway, LipA is replaced by LipS1/S2 identified in this study. An enzyme corresponding to LipB or LipM is still unclear in a number of archaeal species. “H” refers to H-protein in the glycine cleavage system. Lipoic acid-activating enzyme and lipoyl transferase are utilized in mammalian cells instead of LplA. Abbreviations: LipA, classical lipoyl synthase; LipB and LipM, octanoyl transferase; LplA, lipoate-protein ligase; LipS1/S2, archaeal lipoyl synthase.