This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Lipoate Biosynthesis|
Expected Taxonomic Range: Bacteria
Lipoate is an organosulfur compound that contains a ditholane ring, which is a cyclic disulfide. Lipoate is used as an essential cofactor by many enzyme complexes involved in oxidative metabolism, including the pyruvate dehydrogenase complex [Herbert75, Stepp81, Reed93], the 2-oxoglutarate decarboxylation to succinyl-CoA [Herbert75, Stepp81, Reed93], the 2-oxoisovalerate decarboxylation to isobutanoyl-CoA [Reed90], and the glycine cleavage [Vanden91, Reed93].
Each of these enzyme complexes is composed of multiple copies of three enzymes: a substrate-specific decarboxylase-dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2) specific for each type of complex, and a dihydrolipoamide dehydrogenase (E3). The (E2) proteins have a dedicated lipoyl domain. In order for the complex to be active, lipoate must be attached to the lipoyl domain by an amide linkage between its carboxylate moiety and a specific lysine residue in the enzyme [Reed93]..
E1 catalyzes a reaction in which the substrate is attached to the lipoate cofactor and decarboxylated. During this reaction, the lipoate cofactor is reduced to dihydriolipoate. E2 then catalyzes an acyl transfer step, in which the product of the reaction is released. Finally, E3 catalyzes the oxidation of the dihydrolipoyl cofactor back to lipoyl form, with NAD being the ultimate electron acceptor [Reed90].
About This Pathway
The biosynthesis of lipoate is unusual, and shares the same mechanism as the biosynthesis of biotin. The precursor octanoate molecule is first attached to a specific L-lysine residue within the lipoyl domain, and is then converted to lipoate.
In Escherichia coli the pathway consists of two steps - first enzyme in the pathway, encoded by either lplA or lipB, transfers either free octanoate or the octanoate moiety from octanoate-[acp] molecue, respectively, to a specific lysyl residue in any of the lipoate-dependent enzymes, while another enzyme, encoded by lipA, converts the bound octanoate to lipoate (see lipoate biosynthesis and incorporation I and lipoate biosynthesis and incorporation II).
In Bacillus subtilis the pathway is somewhat mnore complex. The first enzyme, encoded by lipM, can transfer the octanoate from octanoyl-[acp] only to the H protein of the glycine cleavage system. Thus, a second enzyme, an amidotransferase encoded by lipL, is required to complete the transfer of the octanoate moiety from the octanoylated GcvH protein to the E2 components of the 2-oxo acid dehydrogenases, where it is converted to lipoate by a LipA enzyme [Christensen11].
Variants: lipoate biosynthesis and incorporation (glycine cleavage system, yeast) , lipoate biosynthesis and incorporation (pyruvate dehydrogenase and oxoglutarate dehydrogenase, yeast) , lipoate biosynthesis and incorporation I , lipoate biosynthesis and incorporation II , lipoate salvage I , lipoate salvage II
Christensen11: Christensen QH, Martin N, Mansilla MC, de Mendoza D, Cronan JE (2011). "A novel amidotransferase required for lipoic acid cofactor assembly in Bacillus subtilis." Mol Microbiol 80(2);350-63. PMID: 21338421
Stepp81: Stepp LR, Bleile DM, McRorie DK, Pettit FH, Reed LJ (1981). "Use of trypsin and lipoamidase to study the role of lipoic acid moieties in the pyruvate and alpha-ketoglutarate dehydrogenase complexes of Escherichia coli." Biochemistry 20(16);4555-60. PMID: 6794598
Vanden91: Vanden Boom TJ, Reed KE, Cronan JE (1991). "Lipoic acid metabolism in Escherichia coli: isolation of null mutants defective in lipoic acid biosynthesis, molecular cloning and characterization of the E. coli lip locus, and identification of the lipoylated protein of the glycine cleavage system." J Bacteriol 173(20);6411-20. PMID: 1655709
Cicchillo04a: Cicchillo RM, Lee KH, Baleanu-Gogonea C, Nesbitt NM, Krebs C, Booker SJ (2004). "Escherichia coli lipoyl synthase binds two distinct [4Fe-4S] clusters per polypeptide." Biochemistry 43(37);11770-81. PMID: 15362861
Cicchillo04b: Cicchillo RM, Iwig DF, Jones AD, Nesbitt NM, Baleanu-Gogonea C, Souder MG, Tu L, Booker SJ (2004). "Lipoyl synthase requires two equivalents of S-adenosyl-L-methionine to synthesize one equivalent of lipoic acid." Biochemistry 43(21);6378-86. PMID: 15157071
Martin09: Martin N, Lombardia E, Altabe SG, de Mendoza D, Mansilla MC (2009). "A lipA (yutB) mutant, encoding lipoic acid synthase, provides insight into the interplay between branched-chain and unsaturated fatty acid biosynthesis in Bacillus subtilis." J Bacteriol 191(24);7447-55. PMID: 19820084
Martin11a: Martin N, Christensen QH, Mansilla MC, Cronan JE, de Mendoza D (2011). "A novel two-gene requirement for the octanoyltransfer reaction of Bacillus subtilis lipoic acid biosynthesis." Mol Microbiol 80(2);335-49. PMID: 21338420
Marvin01: Marvin ME, Williams PH, Cashmore AM (2001). "The isolation and characterisation of a Saccharomyces cerevisiae gene (LIP2) involved in the attachment of lipoic acid groups to mitochondrial enzymes." FEMS Microbiol Lett 199(1);131-6. PMID: 11356580
Miller00: Miller JR, Busby RW, Jordan SW, Cheek J, Henshaw TF, Ashley GW, Broderick JB, Cronan JE, Marletta MA (2000). "Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein." Biochemistry 39(49);15166-78. PMID: 11106496
Smaczynskade04: Smaczynska-de Rooij I, Migdalski A, Rytka J (2004). "Alpha-Ketoglutarate dehydrogenase and lipoic acid synthase are important for the functioning of peroxisomes of Saccharomyces cerevisiae." Cell Mol Biol Lett 9(2);271-86. PMID: 15213808
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