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|
(R)-lipoate is a sulfur-containing cofactor found in many prokaryotic and eukaryotic organisms. It is utilized by several enzymes involved in oxidative metabolism, including the pyruvate dehydrogenase complex [Herbert75, Stepp81, Reed93a], the 2-oxoglutarate decarboxylation to succinyl-CoA [Herbert75, Stepp81, Reed93a], the 2-oxoisovalerate decarboxylation to isobutanoyl-CoA [Reed90], and the glycine cleavage [Vanden91, Reed93a].
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), a flavoprotein that is a common component of these multienzyme complexes. E1 catalyzes both the decarboxylation of the α-keto acid and the subsequent reductive acylation of the lipoyl moiety, which is covalently bound to E2. E2 catalyzes the acyl transfer step, and E3 catalyzes the reoxidation of the dihydrolipoyl moiety with NAD as the ultimate electron acceptor [Reed90]. The lipoate cofactor is bound to the E2 by an amide linkage between its carboxylate moiety and a specific lysine residue in the enzyme [Reed93a].
About This Pathway
In this pathway the enzyme lipoate-protein ligase A (LplA, LplB or LplJ, depending on strain) attaches pre-existing lipoate that has been imported from outside the cell to an E2 enzyme, thus catalyzing a salvage pathway [Morris95]. The pathway has been shown to occur in archaea [Christensen09], bacteria [Morris94, Morris95] and animals [Fujiwara99, Fujiwara01].
It is generally believed that mammals primarily rely on salvaged (R)-lipoate. Even though the genes encoding LipA and LipB have been identified in mammalian genomes, and it has been shown that mammalian cells are capable of synthesizing (R)-lipoate in mitochondria [Morikawa01a], their significance is not fully understood. The ligation of salvaged (R)-lipoate in mammals is performed by a single enzyme, LplA (lipoate protein ligase A), which catalyzes both the activation of (R)-lipoate to a lipoyl-adenylate intermediate, and the ligation of the later to the E2 subunits, as described here [Fujiwara99, Fujiwara01]. A similar enzyme has been characterized in bacteria [Morris94, Morris95].
In most Archaea the enzyme that catalyzes these reactions is a heterodimer, composed of proteins encoded by lplA and lplB genes [Christensen09]. LplB is required for lipoyl-adenylate formation but is not required for transfer of the lipoyl moiety of lipoyl-adenylate to acceptor proteins [Christensen09].
Variants: lipoate biosynthesis and incorporation (yeast), lipoate biosynthesis and incorporation I, lipoate biosynthesis and incorporation II, lipoate biosynthesis and incorporation III (Bacillus), lipoate salvage II
Unification Links: EcoCyc:PWY0-522
Christensen09: Christensen QH, Cronan JE (2009). "The Thermoplasma acidophilum LplA-LplB complex defines a new class of bipartite lipoate-protein ligases." J Biol Chem 284(32);21317-26. PMID: 19520844
Fujiwara01: Fujiwara K, Takeuchi S, Okamura-Ikeda K, Motokawa Y (2001). "Purification, characterization, and cDNA cloning of lipoate-activating enzyme from bovine liver." J Biol Chem 276(31);28819-23. PMID: 11382754
Fujiwara99: Fujiwara K, Suzuki M, Okumachi Y, Okamura-Ikeda K, Fujiwara T, Takahashi E, Motokawa Y (1999). "Molecular cloning, structural characterization and chromosomal localization of human lipoyltransferase gene." Eur J Biochem 260(3);761-7. PMID: 10103005
Morikawa01a: Morikawa T, Yasuno R, Wada H (2001). "Do mammalian cells synthesize lipoic acid? Identification of a mouse cDNA encoding a lipoic acid synthase located in mitochondria." FEBS Lett 498(1);16-21. PMID: 11389890
Morris94: Morris TW, Reed KE, Cronan JE (1994). "Identification of the gene encoding lipoate-protein ligase A of Escherichia coli. Molecular cloning and characterization of the lplA gene and gene product." J Biol Chem 269(23);16091-100. PMID: 8206909
Morris95: Morris TW, Reed KE, Cronan JE (1995). "Lipoic acid metabolism in Escherichia coli: the lplA and lipB genes define redundant pathways for ligation of lipoyl groups to apoprotein." J Bacteriol 177(1);1-10. PMID: 8002607
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
Christensen11a: 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
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Fujiwara05: Fujiwara K, Toma S, Okamura-Ikeda K, Motokawa Y, Nakagawa A, Taniguchi H (2005). "Crystal structure of lipoate-protein ligase A from Escherichia coli. Determination of the lipoic acid-binding site." J Biol Chem 280(39);33645-51. PMID: 16043486
Fujiwara10: Fujiwara K, Maita N, Hosaka H, Okamura-Ikeda K, Nakagawa A, Taniguchi H (2010). "Global conformational change associated with the two-step reaction catalyzed by Escherichia coli lipoate-protein ligase A." J Biol Chem 285(13);9971-80. PMID: 20089862
Hermes09: Hermes FA, Cronan JE (2009). "Scavenging of cytosolic octanoic acid by mutant LplA lipoate ligases allows growth of Escherichia coli strains lacking the LipB octanoyltransferase of lipoic acid synthesis." J Bacteriol 191(22);6796-803. PMID: 19684135
Hermes14: Hermes FA, Cronan JE (2014). "An NAD synthetic reaction bypasses the lipoate requirement for aerobic growth of Escherichia coli strains blocked in succinate catabolism." Mol Microbiol. PMID: 25303731
Kim05: Kim DJ, Kim KH, Lee HH, Lee SJ, Ha JY, Yoon HJ, Suh SW (2005). "Crystal structure of lipoate-protein ligase A bound with the activated intermediate: insights into interaction with lipoyl domains." J Biol Chem 280(45);38081-9. PMID: 16141198
Liu14e: Liu DS, Nivon LG, Richter F, Goldman PJ, Deerinck TJ, Yao JZ, Richardson D, Phipps WS, Ye AZ, Ellisman MH, Drennan CL, Baker D, Ting AY (2014). "Computational design of a red fluorophore ligase for site-specific protein labeling in living cells." Proc Natl Acad Sci U S A 111(43);E4551-9. PMID: 25313043
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