The Enzyme Database

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EC 1.2.1.25     
Accepted name: branched-chain α-keto acid dehydrogenase system
Reaction: 3-methyl-2-oxobutanoate + CoA + NAD+ = 2-methylpropanoyl-CoA + CO2 + NADH
Other name(s): branched-chain α-keto acid dehydrogenase complex; 2-oxoisovalerate dehydrogenase; α-ketoisovalerate dehydrogenase; 2-oxoisovalerate dehydrogenase (acylating)
Systematic name: 3-methyl-2-oxobutanoate:NAD+ 2-oxidoreductase (CoA-methylpropanoylating)
Comments: This enzyme system catalyses the oxidative decarboxylation of branched-chain α-keto acids derived from L-leucine, L-isoleucine, and L-valine to branched-chain acyl-CoAs. It belongs to the 2-oxoacid dehydrogenase system family, which also includes EC 1.2.1.104, pyruvate dehydrogenase system, EC 1.2.1.105, 2-oxoglutarate dehydrogenase system, EC 1.4.1.27, glycine cleavage system, and EC 2.3.1.190, acetoin dehydrogenase system. With the exception of the glycine cleavage system, which contains 4 components, the 2-oxoacid dehydrogenase systems share a common structure, consisting of three main components, namely a 2-oxoacid dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2), and dihydrolipoamide dehydrogenase (E3). The reaction catalysed by this system is the sum of three activities: EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring), EC 2.3.1.168, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase, and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The system also acts on (S)-3-methyl-2-oxopentanoate and 4-methyl-2-oxopentanoate.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 37211-61-3
References:
1.  Namba, Y., Yoshizawa, K., Ejima, A., Hayashi, T. and Kaneda, T. Coenzyme A- and nicotinamide adenine dinucleotide-dependent branched chain α-keto acid dehydrogenase. I. Purification and properties of the enzyme from Bacillus subtilis. J. Biol. Chem. 244 (1969) 4437–4447. [PMID: 4308861]
2.  Pettit, F.H., Yeaman, S.J. and Reed, L.J. Purification and characterization of branched chain α-keto acid dehydrogenase complex of bovine kidney. Proc. Natl. Acad. Sci. USA 75 (1978) 4881–4885. [DOI] [PMID: 283398]
3.  Harris, R.A., Hawes, J.W., Popov, K.M., Zhao, Y., Shimomura, Y., Sato, J., Jaskiewicz, J. and Hurley, T.D. Studies on the regulation of the mitochondrial α-ketoacid dehydrogenase complexes and their kinases. Adv. Enzyme Regul. 37 (1997) 271–293. [DOI] [PMID: 9381974]
4.  Evarsson, A., Chuang, J.L., Wynn, R.M., Turley, S., Chuang, D.T. and Hol, W.G. Crystal structure of human branched-chain α-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease. Structure 8 (2000) 277–291. [PMID: 10745006]
5.  Reed, L.J. A trail of research from lipoic acid to α-keto acid dehydrogenase complexes. J. Biol. Chem. 276 (2001) 38329–38336. [DOI] [PMID: 11477096]
[EC 1.2.1.25 created 1972, modified 2019, modified 2020]
 
 
EC 1.2.1.105     
Accepted name: 2-oxoglutarate dehydrogenase system
Reaction: 2-oxoglutarate + CoA + NAD+ = succinyl-CoA + CO2 + NADH
Other name(s): 2-oxoglutarate dehydrogenase complex
Systematic name: 2-oxoglutarate:NAD+ 2-oxidoreductase (CoA-succinylating)
Comments: The 2-oxoglutarate dehydrogenase system is a large enzyme complex that belongs to the 2-oxoacid dehydrogenase system family, which also includes EC 1.2.1.25, branched-chain α-keto acid dehydrogenase system, EC 1.2.1.104, pyruvate dehydrogenase system, EC 1.4.1.27, glycine cleavage system, and EC 2.3.1.190, acetoin dehydrogenase system. With the exception of the glycine cleavage system, which contains 4 components, the 2-oxoacid dehydrogenase systems share a common structure, consisting of three main components, namely a 2-oxoacid dehydrogenase (E1), a dihydrolipoamide acyltransferase (E2), and a dihydrolipoamide dehydrogenase (E3). This enzyme system converts 2-oxoglutarate to succinyl-CoA and produces NADH and CO2 in a complicated series of irreversible reactions. The reaction catalysed by this system is the sum of three activities: EC 1.2.4.2, oxoglutarate dehydrogenase (succinyl-transferring) (E1), EC 2.3.1.61, dihydrolipoyllysine-residue succinyltransferase (E2) and EC 1.8.1.4, dihydrolipoyl dehydrogenase (E3).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Robien, M.A., Clore, G.M., Omichinski, J.G., Perham, R.N., Appella, E., Sakaguchi, K. and Gronenborn, A.M. Three-dimensional solution structure of the E3-binding domain of the dihydrolipoamide succinyltransferase core from the 2-oxoglutarate dehydrogenase multienzyme complex of Escherichia coli. Biochemistry 31 (1992) 3463–3471. [DOI] [PMID: 1554728]
2.  Knapp, J.E., Mitchell, D.T., Yazdi, M.A., Ernst, S.R., Reed, L.J. and Hackert, M.L. Crystal structure of the truncated cubic core component of the Escherichia coli 2-oxoglutarate dehydrogenase multienzyme complex. J. Mol. Biol. 280 (1998) 655–668. [DOI] [PMID: 9677295]
3.  Reed, L.J. A trail of research from lipoic acid to α-keto acid dehydrogenase complexes. J. Biol. Chem. 276 (2001) 38329–38336. [DOI] [PMID: 11477096]
4.  Murphy, G.E. and Jensen, G.J. Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes. Structure 13 (2005) 1765–1773. [DOI] [PMID: 16338405]
5.  Frank, R.A., Price, A.J., Northrop, F.D., Perham, R.N. and Luisi, B.F. Crystal structure of the E1 component of the Escherichia coli 2-oxoglutarate dehydrogenase multienzyme complex. J. Mol. Biol. 368 (2007) 639–651. [DOI] [PMID: 17367808]
6.  Bunik, V.I. and Degtyarev, D. Structure-function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins. Proteins 71 (2008) 874–890. [DOI] [PMID: 18004749]
7.  Shim da, J., Nemeria, N.S., Balakrishnan, A., Patel, H., Song, J., Wang, J., Jordan, F. and Farinas, E.T. Assignment of function to histidines 260 and 298 by engineering the E1 component of the Escherichia coli 2-oxoglutarate dehydrogenase complex; substitutions that lead to acceptance of substrates lacking the 5-carboxyl group. Biochemistry 50 (2011) 7705–7709. [DOI] [PMID: 21809826]
[EC 1.2.1.105 created 2020]
 
 
EC 1.3.1.118     
Accepted name: meromycolic acid enoyl-[acyl-carrier-protein] reductase
Reaction: a meromycolyl-[acyl-carrier protein] + NAD+ = a trans2-meromycolyl-[acyl-carrier protein] + NADH + H+
Glossary: meromycolic acids are one of the two precursors of the mycolic acids produced by Mycobacteria. They consist of a long chain typically of 50–60 carbons, which is functionalized by different groups.
Other name(s): inhA (gene name)
Systematic name: meromycolyl-[acyl-carrier protein]:NAD+ oxidoreductase
Comments: InhA is a component of the fatty acid synthase (FAS) II system of Mycobacterium tuberculosis, catalysing an enoyl-[acyl-carrier-protein] reductase step. The enzyme acts on very long and unsaturated fatty acids that form the meromycolic component of mycolic acids. It extends FASI-derived C20 fatty acids to form C60 to C90 mycolic acids. The enzyme, which forms a homotetramer, is the target of the preferred antitubercular drug isoniazid.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Quemard, A., Sacchettini, J.C., Dessen, A., Vilcheze, C., Bittman, R., Jacobs, W.R., Jr. and Blanchard, J.S. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 34 (1995) 8235–8241. [PMID: 7599116]
2.  Rozwarski, D.A., Vilcheze, C., Sugantino, M., Bittman, R. and Sacchettini, J.C. Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J. Biol. Chem. 274 (1999) 15582–15589. [PMID: 10336454]
3.  Marrakchi, H., Laneelle, G. and Quemard, A. InhA, a target of the antituberculous drug isoniazid, is involved in a mycobacterial fatty acid elongation system, FAS-II. Microbiology 146 (2000) 289–296. [PMID: 10708367]
4.  Vilcheze, C., Morbidoni, H.R., Weisbrod, T.R., Iwamoto, H., Kuo, M., Sacchettini, J.C. and Jacobs, W.R., Jr. Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J. Bacteriol. 182 (2000) 4059–4067. [PMID: 10869086]
5.  Gurvitz, A., Hiltunen, J.K. and Kastaniotis, A.J. Function of heterologous Mycobacterium tuberculosis InhA, a type 2 fatty acid synthase enzyme involved in extending C20 fatty acids to C60-to-C90 mycolic acids, during de novo lipoic acid synthesis in Saccharomyces cerevisiae. Appl. Environ. Microbiol. 74 (2008) 5078–5085. [PMID: 18552191]
6.  Chollet, A., Mourey, L., Lherbet, C., Delbot, A., Julien, S., Baltas, M., Bernadou, J., Pratviel, G., Maveyraud, L. and Bernardes-Genisson, V. Crystal structure of the enoyl-ACP reductase of Mycobacterium tuberculosis (InhA) in the apo-form and in complex with the active metabolite of isoniazid pre-formed by a biomimetic approach. J. Struct. Biol. 190 (2015) 328–337. [PMID: 25891098]
[EC 1.3.1.118 created 2018]
 
 
EC 1.4.1.27     
Accepted name: glycine cleavage system
Reaction: glycine + tetrahydrofolate + NAD+ = 5,10-methylenetetrahydrofolate + NH3 + CO2 + NADH
Other name(s): GCV
Systematic name: glycine:NAD+ 2-oxidoreductase (tetrahydrofolate-methylene-adding)
Comments: The glycine cleavage (GCV) system is a large multienzyme complex that belongs to the 2-oxoacid dehydrogenase complex family, which also includes EC 1.2.1.25, branched-chain α-keto acid dehydrogenase system, EC 1.2.1.105, 2-oxoglutarate dehydrogenase system, EC 1.2.1.104, pyruvate dehydrogenase system, and EC 2.3.1.190, acetoin dehydrogenase system. The GCV system catalyses the reversible oxidation of glycine, yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate and a reduced pyridine nucleotide. Tetrahydrofolate serves as a recipient for one-carbon units generated during glycine cleavage to form the methylene group. The GCV system consists of four protein components, the P protein (EC 1.4.4.2, glycine dehydrogenase (aminomethyl-transferring)), T protein (EC 2.1.2.10, aminomethyltransferase), L protein (EC 1.8.1.4, dihydrolipoyl dehydrogenase), and the non-enzyme H protein (lipoyl-carrier protein). The P protein catalyses the pyridoxal phosphate-dependent liberation of CO2 from glycine, leaving a methylamine moiety. The methylamine moiety is transferred to the lipoic acid group of the H protein, which is bound to the P protein prior to decarboxylation of glycine. The T protein catalyses the release of ammonia from the methylamine group and transfers the remaining C1 unit to tetrahydrofolate, forming 5,10-methylenetetrahydrofolate. The L protein then oxidizes the lipoic acid component of the H protein and transfers the electrons to NAD+, forming NADH.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Motokawa, Y. and Kikuchi, G. Glycine metabolism by rat liver mitochondria. Reconstruction of the reversible glycine cleavage system with partially purified protein components. Arch. Biochem. Biophys. 164 (1974) 624–633. [DOI] [PMID: 4460882]
2.  Hiraga, K. and Kikuchi, G. The mitochondrial glycine cleavage system. Functional association of glycine decarboxylase and aminomethyl carrier protein. J. Biol. Chem. 255 (1980) 11671–11676. [PMID: 7440563]
3.  Okamura-Ikeda, K., Fujiwara, K. and Motokawa, Y. Purification and characterization of chicken liver T-protein, a component of the glycine cleavage system. J. Biol. Chem. 257 (1982) 135–139. [PMID: 7053363]
4.  Fujiwara, K., Okamura-Ikeda, K. and Motokawa, Y. Mechanism of the glycine cleavage reaction. Further characterization of the intermediate attached to H-protein and of the reaction catalyzed by T-protein. J. Biol. Chem. 259 (1984) 10664–10668. [PMID: 6469978]
5.  Okamura-Ikeda, K., Ohmura, Y., Fujiwara, K. and Motokawa, Y. Cloning and nucleotide sequence of the gcv operon encoding the Escherichia coli glycine-cleavage system. Eur. J. Biochem. 216 (1993) 539–548. [DOI] [PMID: 8375392]
[EC 1.4.1.27 created 2020]
 
 
EC 1.8.1.4     
Accepted name: dihydrolipoyl dehydrogenase
Reaction: protein N6-(dihydrolipoyl)lysine + NAD+ = protein N6-(lipoyl)lysine + NADH + H+
For diagram of glycine cleavage system, click here, for diagram of the citric acid cycle, click here and for diagram of oxo-acid dehydrogenase complexes, click here
Glossary: dihydrolipoyl = (6R)-6,8-disulfanyloctanoyl
For structure of dihydrolipoyl, click here
Other name(s): LDP-Glc; LDP-Val; dehydrolipoate dehydrogenase; diaphorase; dihydrolipoamide dehydrogenase; dihydrolipoamide:NAD+ oxidoreductase; dihydrolipoic dehydrogenase; dihydrothioctic dehydrogenase; lipoamide dehydrogenase (NADH); lipoamide oxidoreductase (NADH); lipoamide reductase; lipoamide reductase (NADH); lipoate dehydrogenase; lipoic acid dehydrogenase; lipoyl dehydrogenase; protein-6-N-(dihydrolipoyl)lysine:NAD+ oxidoreductase
Systematic name: protein-N6-(dihydrolipoyl)lysine:NAD+ oxidoreductase
Comments: A flavoprotein (FAD). A component of the multienzyme 2-oxo-acid dehydrogenase complexes. In the pyruvate dehydrogenase complex, it binds to the core of EC 2.3.1.12, dihydrolipoyllysine-residue acetyltransferase, and catalyses oxidation of its dihydrolipoyl groups. It plays a similar role in the oxoglutarate and 3-methyl-2-oxobutanoate dehydrogenase complexes. Another substrate is the dihydrolipoyl group in the H-protein of the glycine-cleavage system (click here for diagram), in which it acts, together with EC 1.4.4.2, glycine dehydrogenase (decarboxylating), and EC 2.1.2.10, aminomethyltransferase, to break down glycine. It can also use free dihydrolipoate, dihydrolipoamide or dihydrolipoyllysine as substrate. This enzyme was first shown to catalyse the oxidation of NADH by methylene blue; this activity was called diaphorase. The glycine cleavage system is composed of four components that only loosely associate: the P protein (EC 1.4.4.2), the T protein (EC 2.1.2.10), the L protein (EC 1.8.1.4) and the lipoyl-bearing H protein [6].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9001-18-7
References:
1.  Massey, V. Lipoyl dehydrogenase. In: Boyer, P.D., Lardy, H. and Myrbäck, K. (Ed.), The Enzymes, 2nd edn, vol. 7, Academic Press, New York, 1963, pp. 275–306.
2.  Massey, V., Gibson, Q.H. and Veeger, C. Intermediates in the catalytic action of lipoyl dehydrogenase (diaphorase). Biochem. J. 77 (1960) 341–351. [PMID: 13767908]
3.  Savage, N. Preparation and properties of highly purified diaphorase. Biochem. J. 67 (1957) 146–155. [PMID: 13471525]
4.  Straub, F.B. Isolation and properties of a flavoprotein from heart muscle tissue. Biochem. J. 33 (1939) 787–792. [PMID: 16746974]
5.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
6.  Nesbitt, N.M., Baleanu-Gogonea, C., Cicchillo, R.M., Goodson, K., Iwig, D.F., Broadwater, J.A., Haas, J.A., Fox, B.G. and Booker, S.J. Expression, purification, and physical characterization of Escherichia coli lipoyl(octanoyl)transferase. Protein Expr. Purif. 39 (2005) 269–282. [DOI] [PMID: 15642479]
[EC 1.8.1.4 created 1961 as EC 1.6.4.3, modified 1976, transferred 1983 to EC 1.8.1.4, modified 2003, modified 2006]
 
 
EC 2.3.1.11     
Accepted name: thioethanolamine S-acetyltransferase
Reaction: acetyl-CoA + 2-aminoethanethiol = CoA + S-(2-aminoethyl)thioacetate
Other name(s): thioltransacetylase B; thioethanolamine acetyltransferase; acetyl-CoA:thioethanolamine S-acetyltransferase
Systematic name: acetyl-CoA:2-aminoethanethiol S-acetyltransferase
Comments: 2-Sulfanylethan-1-ol (2-mercaptoethanol) can act as a substrate [1].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 9029-93-0
References:
1.  Brady, R.O. and Stadtman, E.R. Enzymatic thioltransacetylation. J. Biol. Chem. 211 (1954) 621–629. [PMID: 13221570]
2.  Gunsalus, I.C. Group transfer and acyl-generating functions of lipoic acid derivatives. In: McElroy, W.D. and Glass, B. (Ed.), A Symposium on the Mechanism of Enzyme Action, Johns Hopkins Press, Baltimore, 1954, pp. 545–580.
[EC 2.3.1.11 created 1961, modified 2006]
 
 
EC 2.3.1.12     
Accepted name: dihydrolipoyllysine-residue acetyltransferase
Reaction: acetyl-CoA + enzyme N6-(dihydrolipoyl)lysine = CoA + enzyme N6-(S-acetyldihydrolipoyl)lysine
For diagram of oxo-acid-dehydrogenase complexes, click here
Glossary: dihydrolipoyl group
Other name(s): acetyl-CoA:dihydrolipoamide S-acetyltransferase; dihydrolipoamide S-acetyltransferase; dihydrolipoate acetyltransferase; dihydrolipoic transacetylase; dihydrolipoyl acetyltransferase; lipoate acetyltransferase; lipoate transacetylase; lipoic acetyltransferase; lipoic acid acetyltransferase; lipoic transacetylase; lipoylacetyltransferase; thioltransacetylase A; transacetylase X; enzyme-dihydrolipoyllysine:acetyl-CoA S-acetyltransferase; acetyl-CoA:enzyme 6-N-(dihydrolipoyl)lysine S-acetyltransferase
Systematic name: acetyl-CoA:enzyme N6-(dihydrolipoyl)lysine S-acetyltransferase
Comments: A multimer (24-mer or 60-mer, depending on the source) of this enzyme forms the core of the pyruvate dehydrogenase multienzyme complex, and binds tightly both EC 1.2.4.1, pyruvate dehydrogenase (acetyl-transferring) and EC 1.8.1.4, dihydrolipoyl dehydrogenase. The lipoyl group of this enzyme is reductively acetylated by EC 1.2.4.1, and the only observed direction catalysed by EC 2.3.1.12 is that where the acetyl group is passed to coenzyme A.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9032-29-5
References:
1.  Brady, R.O. and Stadtman, E.R. Enzymatic thioltransacetylation. J. Biol. Chem. 211 (1954) 621–629. [PMID: 13221570]
2.  Gunsalus, I.C. Group transfer and acyl-generating functions of lipoic acid derivatives. In: McElroy, W.D. and Glass, B. (Ed.), A Symposium on the Mechanism of Enzyme Action, Johns Hopkins Press, Baltimore, 1954, pp. 545–580.
3.  Gunsalus, I.C., Barton, L.S. and Gruber, W. Biosynthesis and structure of lipoic acid derivatives. J. Am. Chem. Soc. 78 (1956) 1763–1766.
4.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
[EC 2.3.1.12 created 1961, modified 2003]
 
 
EC 2.3.1.181     
Accepted name: lipoyl(octanoyl) transferase
Reaction: an octanoyl-[acyl-carrier protein] + a protein = a protein N6-(octanoyl)lysine + an [acyl-carrier protein]
Glossary: lipoyl group
Other name(s): LipB; lipoyl (octanoyl)-[acyl-carrier-protein]-protein N-lipoyltransferase; lipoyl (octanoyl)-acyl carrier protein:protein transferase; lipoate/octanoate transferase; lipoyltransferase; octanoyl-[acyl carrier protein]-protein N-octanoyltransferase; lipoyl(octanoyl)transferase; octanoyl-[acyl-carrier-protein]:protein N-octanoyltransferase
Systematic name: octanoyl-[acyl-carrier protein]:protein N-octanoyltransferase
Comments: This is the first committed step in the biosynthesis of lipoyl cofactor. Lipoylation is essential for the function of several key enzymes involved in oxidative metabolism, as it converts apoprotein into the biologically active holoprotein. Examples of such lipoylated proteins include pyruvate dehydrogenase (E2 domain), 2-oxoglutarate dehydrogenase (E2 domain), the branched-chain 2-oxoacid dehydrogenases and the glycine cleavage system (H protein) [2,3]. Lipoyl-ACP can also act as a substrate [4] although octanoyl-ACP is likely to be the true substrate [6]. The other enzyme involved in the biosynthesis of lipoyl cofactor is EC 2.8.1.8, lipoyl synthase. An alternative lipoylation pathway involves EC 6.3.1.20, lipoate—protein ligase, which can lipoylate apoproteins using exogenous lipoic acid (or its analogues).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 392687-64-8
References:
1.  Nesbitt, N.M., Baleanu-Gogonea, C., Cicchillo, R.M., Goodson, K., Iwig, D.F., Broadwater, J.A., Haas, J.A., Fox, B.G. and Booker, S.J. Expression, purification, and physical characterization of Escherichia coli lipoyl(octanoyl)transferase. Protein Expr. Purif. 39 (2005) 269–282. [DOI] [PMID: 15642479]
2.  Vanden Boom, T.J., Reed, K.E. and Cronan, J.E., Jr. 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 (1991) 6411–6420. [DOI] [PMID: 1655709]
3.  Jordan, S.W. and Cronan, J.E., Jr. A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria. J. Biol. Chem. 272 (1997) 17903–17906. [DOI] [PMID: 9218413]
4.  Zhao, X., Miller, J.R., Jiang, Y., Marletta, M.A. and Cronan, J.E. Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem. Biol. 10 (2003) 1293–1302. [DOI] [PMID: 14700636]
5.  Wada, M., Yasuno, R., Jordan, S.W., Cronan, J.E., Jr. and Wada, H. Lipoic acid metabolism in Arabidopsis thaliana: cloning and characterization of a cDNA encoding lipoyltransferase. Plant Cell Physiol. 42 (2001) 650–656. [PMID: 11427685]
6.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
[EC 2.3.1.181 created 2006, modified 2016]
 
 
EC 2.3.1.200     
Accepted name: lipoyl amidotransferase
Reaction: [glycine cleavage system H]-N6-lipoyl-L-lysine + a [lipoyl-carrier protein] = glycine cleavage system H + a [lipoyl-carrier protein]-N6-lipoyl-L-lysine
Glossary: lipoic acid = 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid
Other name(s): LipL (gene name, ambiguous)
Systematic name: [glycine cleavage system H]-N6-lipoyl-L-lysine:[lipoyl-carrier protein]-N6-L-lysine lipoyltransferase
Comments: In the bacterium Listeria monocytogenes the enzyme takes part in a pathway for scavenging of lipoic acid. The enzyme is bound to 2-oxo-acid dehydrogenases such as the pyruvate dehydrogenase complex, where it transfers the lipoyl moiety from lipoyl-[glycine cleavage system H] to the E2 subunits of the complexes.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Christensen, Q.H., Hagar, J.A., O'Riordan, M.X. and Cronan, J.E. A complex lipoate utilization pathway in Listeria monocytogenes. J. Biol. Chem. 286 (2011) 31447–31456. [DOI] [PMID: 21768091]
[EC 2.3.1.200 created 2012]
 
 
EC 2.3.1.204     
Accepted name: octanoyl-[GcvH]:protein N-octanoyltransferase
Reaction: [glycine cleavage system H]-N6-octanoyl-L-lysine + a [lipoyl-carrier protein] = glycine cleavage system H + a [lipoyl-carrier protein]-N6-octanoyl-L-lysine
Glossary: GcvH = glycine cleavage system H]
Other name(s): LipL; octanoyl-[GcvH]:E2 amidotransferase; ywfL (gene name)
Systematic name: [glycine cleavage system H]-N6-octanoyl-L-lysine:[lipoyl-carrier protein]-N6-L-lysine octanoyltransferase
Comments: In the bacterium Bacillus subtilis it has been shown that the enzyme catalyses the amidotransfer of the octanoyl moiety from [glycine cleavage system H]-N6-octanoyl-L-lysine (i.e. octanoyl-GcvH) to the E2 subunit (dihydrolipoamide acetyltransferase) of pyruvate dehydrogenase.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc
References:
1.  Christensen, Q.H., Martin, N., Mansilla, M.C., de Mendoza, D. and Cronan, J.E. A novel amidotransferase required for lipoic acid cofactor assembly in Bacillus subtilis. Mol. Microbiol. 80 (2011) 350–363. [DOI] [PMID: 21338421]
2.  Martin, N., Christensen, Q.H., Mansilla, M.C., Cronan, J.E. and de Mendoza, D. A novel two-gene requirement for the octanoyltransfer reaction of Bacillus subtilis lipoic acid biosynthesis. Mol. Microbiol. 80 (2011) 335–349. [DOI] [PMID: 21338420]
[EC 2.3.1.204 created 2012]
 
 
EC 2.7.7.63      
Transferred entry: lipoate—protein ligase, now EC EC 6.3.1.20, lipoate—protein ligase.
[EC 2.7.7.63 created 2006, deleted 2016]
 
 
EC 2.7.11.4     
Accepted name: [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase
Reaction: ATP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] = ADP + [3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphate
Other name(s): BCK; BCKD kinase; BCODH kinase; branched-chain α-ketoacid dehydrogenase kinase; branched-chain 2-oxo acid dehydrogenase kinase; branched-chain keto acid dehydrogenase kinase; branched-chain oxo acid dehydrogenase kinase (phosphorylating); STK2
Systematic name: ATP:[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] phosphotransferase
Comments: The enzyme has no activating compound but is specific for its substrate. It is a mitochondrial enzyme associated with the branched-chain 2-oxoacid dehydrogenase complex. Phosphorylation inactivates EC 1.2.4.4, 3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 82391-38-6
References:
1.  Paxton, R. and Harris, R.A. Isolation of rabbit liver branched chain α-ketoacid dehydrogenase and regulation by phosphorylation. J. Biol. Chem. 257 (1982) 14433–14439. [PMID: 7142221]
2.  Wynn, R.M., Chuang, J.L., Cote, C.D. and Chuang, D.T. Tetrameric assembly and conservation in the ATP-binding domain of rat branched-chain α-ketoacid dehydrogenase kinase. J. Biol. Chem. 275 (2000) 30512–30519. [DOI] [PMID: 10903321]
3.  Chuang, J.L., Wynn, R.M. and Chuang, D.T. The C-terminal hinge region of lipoic acid-bearing domain of E2b is essential for domain interaction with branched-chain α-keto acid dehydrogenase kinase. J. Biol. Chem. 277 (2002) 36905–36908. [DOI] [PMID: 12189132]
4.  Popov, K.M., Hawes, J.W. and Harris, R.A. Mitochondrial α-ketoacid dehydrogenase kinases: a new family of protein kinases. Adv. Second Messenger Phosphoprotein Res. 31 (1997) 105–111. [PMID: 9344245]
[EC 2.7.11.4 created 1986 as EC 2.7.1.115, transferred 2005 to EC 2.7.11.4]
 
 
EC 2.8.1.2     
Accepted name: 3-mercaptopyruvate sulfurtransferase
Reaction: 2-oxo-3-sulfanylpropanoate + reduced thioredoxin = pyruvate + hydrogen sulfide + oxidized thioredoxin (overall reaction)
(1a) 2-oxo-3-sulfanylpropanoate + [3-mercaptopyruvate sulfurtransferase]-L-cysteine = pyruvate + [3-mercaptopyruvate sulfurtransferase]-S-sulfanyl-L-cysteine
(1b) [3-mercaptopyruvate sulfurtransferase]-S-sulfanyl-L-cysteine + reduced thioredoxin = hydrogen sulfide + [3-mercaptopyruvate sulfurtransferase]-L-cysteine + oxidized thioredoxin
Glossary: 2-oxo-3-sulfanylpropanoate = 3-mercaptopyruvate (deprecated)
Other name(s): β-mercaptopyruvate sulfurtransferase; TUM1 (gene name); MPST (gene name); 3-mercaptopyruvate:cyanide sulfurtransferase
Systematic name: 2-oxo-3-sulfanylpropanoate:sulfide sulfurtransferase
Comments: The enzyme catalyses a transsulfuration reaction from 2-oxo-3-sulfanylpropanoate to an internal cysteine residue. In the presence of a dithiol such as reduced thioredoxin or dihydrolipoate, the sulfanyl sulfur is released as hydrogen sulfide. The enzyme participates in a sulfur relay process that leads to the 2-thiolation of some tRNAs and to protein urmylation by transferring sulfur between the NFS1 cysteine desulfurase (EC 2.8.1.7) and the MOCS3 sulfurtransferase (EC 2.8.1.11).
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9026-05-5
References:
1.  Fiedler, H. and Wood, J.L. Specificity studies on the β-mercaptopyruvate-cyanide transsulfuration system. J. Biol. Chem. 222 (1956) 387–397. [PMID: 13367011]
2.  Sörbo, B.H. Enzymic transfer of sulfur from mercaptopyruvate to sulfite or sulfinates. Biochem. Biophys. Acta 24 (1957) 324–329. [PMID: 13436433]
3.  Hylin, J.W. and Wood, J.L. Enzymatic formation of polysulfides from mercaptopyruvate. J. Biol. Chem. 234 (1959) 2141–2144. [PMID: 13673028]
4.  van den Hamer, C.J.A., Morell, A.G. and Scheinberg, H.I. A study of the copper content of β-mercaptopyruvate trans-sulfurase. J. Biol. Chem. 242 (1967) 2514–2516. [PMID: 6026243]
5.  Vachek, H. and Wood, J.L. Purification and properties of mercaptopyruvate sulfur transferase of Escherichia coli. Biochim. Biophys. Acta 258 (1972) 133–146. [DOI] [PMID: 4550801]
6.  Nagahara, N. and Katayama, A. Post-translational regulation of mercaptopyruvate sulfurtransferase via a low redox potential cysteine-sulfenate in the maintenance of redox homeostasis. J. Biol. Chem. 280 (2005) 34569–34576. [DOI] [PMID: 16107337]
7.  Shibuya, N., Tanaka, M., Yoshida, M., Ogasawara, Y., Togawa, T., Ishii, K. and Kimura, H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11 (2009) 703–714. [DOI] [PMID: 18855522]
8.  Mikami, Y., Shibuya, N., Kimura, Y., Nagahara, N., Ogasawara, Y. and Kimura, H. Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem. J. 439 (2011) 479–485. [DOI] [PMID: 21732914]
[EC 2.8.1.2 created 1961, modified 2018]
 
 
EC 2.8.1.8     
Accepted name: lipoyl synthase
Reaction: [protein]-N6-(octanoyl)-L-lysine + an [Fe-S] cluster scaffold protein carrying a [4Fe-4S]2+ cluster + 2 S-adenosyl-L-methionine + 2 oxidized [2Fe-2S] ferredoxin + 6 H+ = [protein]-N6-[(R)-dihydrolipoyl]-L-lysine + an [Fe-S] cluster scaffold protein + 2 sulfide + 4 Fe3+ + 2 L-methionine + 2 5′-deoxyadenosine + 2 reduced [2Fe-2S] ferredoxin
Other name(s): lipA (gene name); LS; lipoate synthase; protein 6-N-(octanoyl)lysine:sulfur sulfurtransferase; protein N6-(octanoyl)lysine:sulfur sulfurtransferase; protein N6-(octanoyl)lysine:sulfur-(sulfur carrier) sulfurtransferase
Systematic name: [protein]-N6-(octanoyl)-L-lysine:an [Fe-S] cluster scaffold protein carrying a [4Fe-4S]2+ cluster sulfurtransferase
Comments: This enzyme catalyses the final step in the de-novo biosynthesis of the lipoyl cofactor, the attachment of two sulfhydryl groups to C6 and C8 of a pendant octanoyl chain. It is a member of the ‘AdoMet radical’ (radical SAM) family, all members of which produce the 5′-deoxyadenosin-5′-yl radical and methionine from AdoMet (S-adenosylmethionine) by the addition of an electron from an iron-sulfur centre. The enzyme contains two [4Fe-4S] clusters. The first cluster produces the radicals, which are converted into 5′-deoxyadenosine when they abstract hydrogen atoms from C6 and C8, respectively, leaving reactive radicals at these positions that interact with sulfur atoms within the second (auxiliary) cluster. Having donated two sulfur atoms, the auxiliary cluster is degraded during catalysis, but is regenerated immediately by the transfer of a new cluster from iron-sulfur cluster carrier proteins [8]. Lipoylation is essential for the function of several key enzymes involved in oxidative metabolism, as it converts apoprotein into the biologically active holoprotein. Examples of such lipoylated proteins include pyruvate dehydrogenase (E2 domain), 2-oxoglutarate dehydrogenase (E2 domain), the branched-chain 2-oxoacid dehydrogenases and the glycine cleavage system (H protein) [1,2]. An alternative lipoylation pathway involves EC 6.3.1.20, lipoate—protein ligase, which can lipoylate apoproteins using exogenous lipoic acid (or its analogues) [4].
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 189398-80-9
References:
1.  Cicchillo, R.M. and Booker, S.J. Mechanistic investigations of lipoic acid biosynthesis in Escherichia coli: both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide. J. Am. Chem. Soc. 127 (2005) 2860–2861. [DOI] [PMID: 15740115]
2.  Vanden Boom, T.J., Reed, K.E. and Cronan, J.E., Jr. 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 (1991) 6411–6420. [DOI] [PMID: 1655709]
3.  Zhao, X., Miller, J.R., Jiang, Y., Marletta, M.A. and Cronan, J.E. Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem. Biol. 10 (2003) 1293–1302. [DOI] [PMID: 14700636]
4.  Cicchillo, R.M., Iwig, D.F., Jones, A.D., Nesbitt, N.M., Baleanu-Gogonea, C., Souder, M.G., Tu, L. and Booker, S.J. Lipoyl synthase requires two equivalents of S-adenosyl-L-methionine to synthesize one equivalent of lipoic acid. Biochemistry 43 (2004) 6378–6386. [DOI] [PMID: 15157071]
5.  Jordan, S.W. and Cronan, J.E., Jr. A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria. J. Biol. Chem. 272 (1997) 17903–17906. [DOI] [PMID: 9218413]
6.  Miller, J.R., Busby, R.W., Jordan, S.W., Cheek, J., Henshaw, T.F., Ashley, G.W., Broderick, J.B., Cronan, J.E., Jr. and Marletta, M.A. Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein. Biochemistry 39 (2000) 15166–15178. [DOI] [PMID: 11106496]
7.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
8.  McCarthy, E.L. and Booker, S.J. Destruction and reformation of an iron-sulfur cluster during catalysis by lipoyl synthase. Science 358 (2017) 373–377. [DOI] [PMID: 29051382]
[EC 2.8.1.8 created 2006, modified 2014, modified 2018]
 
 
EC 6.3.1.20     
Accepted name: lipoate—protein ligase
Reaction: ATP + (R)-lipoate + a [lipoyl-carrier protein]-L-lysine = a [lipoyl-carrier protein]-N6-(lipoyl)lysine + AMP + diphosphate (overall reaction)
(1a) ATP + (R)-lipoate = lipoyl-AMP + diphosphate
(1b) lipoyl-AMP + a [lipoyl-carrier protein]-L-lysine = a [lipoyl-carrier protein]-N6-(lipoyl)lysine + AMP
Other name(s): lplA (gene name); lplJ (gene name); lipoate protein ligase; lipoate-protein ligase A; LPL; LPL-B
Systematic name: [lipoyl-carrier protein]-L-lysine:lipoate ligase (AMP-forming)
Comments: Requires Mg2+. This enzyme participates in lipoate salvage, and is responsible for lipoylation in the presence of exogenous lipoic acid [7]. The enzyme attaches lipoic acid to the lipoyl domains of certain key enzymes involved in oxidative metabolism, including pyruvate dehydrogenase (E2 domain), 2-oxoglutarate dehydrogenase (E2 domain), the branched-chain 2-oxoacid dehydrogenases and the glycine cleavage system (H protein) [6]. Lipoylation is essential for the function of these enzymes. The enzyme can also use octanoate instead of lipoate.
Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 144114-18-1
References:
1.  Morris, T.W., Reed, K.E. and Cronan, J.E., Jr. 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 (1994) 16091–16100. [PMID: 8206909]
2.  Green, D.E., Morris, T.W., Green, J., Cronan, J.E., Jr. and Guest, J.R. Purification and properties of the lipoate protein ligase of Escherichia coli. Biochem. J. 309 (1995) 853–862. [PMID: 7639702]
3.  Zhao, X., Miller, J.R., Jiang, Y., Marletta, M.A. and Cronan, J.E. Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem. Biol. 10 (2003) 1293–1302. [DOI] [PMID: 14700636]
4.  Kim do, J., Kim, K.H., Lee, H.H., Lee, S.J., Ha, J.Y., Yoon, H.J. and Suh, S.W. Crystal structure of lipoate-protein ligase A bound with the activated intermediate: insights into interaction with lipoyl domains. J. Biol. Chem. 280 (2005) 38081–38089. [DOI] [PMID: 16141198]
5.  Fujiwara, K., Toma, S., Okamura-Ikeda, K., Motokawa, Y., Nakagawa, A. and Taniguchi, H. Crystal structure of lipoate-protein ligase A from Escherichia coli. Determination of the lipoic acid-binding site. J. Biol. Chem. 280 (2005) 33645–33651. [DOI] [PMID: 16043486]
6.  Jordan, S.W. and Cronan, J.E., Jr. A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria. J. Biol. Chem. 272 (1997) 17903–17906. [DOI] [PMID: 9218413]
7.  Perham, R.N. Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions. Annu. Rev. Biochem. 69 (2000) 961–1004. [DOI] [PMID: 10966480]
[EC 6.3.1.20 created 2006 as EC 2.7.7.63, transferred 2016 to EC 6.3.1.20]
 
 


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