IUBMB Enzyme Nomenclature

EC 2.8.1.8

Accepted name: lipoyl synthase

Reaction: protein N6-(octanoyl)lysine + 2 sulfur-(sulfur carrier) + 2 S-adenosyl-L-methionine = protein N6-(lipoyl)lysine + 2 (sulfur carrier) + 2 L-methionine + 2 5′-deoxyadenosine

Other name(s): LS; LipA; lipoate synthase; protein 6-N-(octanoyl)lysine:sulfur sulfurtransferase; protein N6-(octanoyl)lysine:sulfur sulfurtransferase

Systematic name: protein N6-(octanoyl)lysine:sulfur-(sulfur carrier) sulfurtransferase

Comments: This enzyme is a member of the 'radical SAM' (S-adenosylmethionine; AdoMet) family, all members of which contain the motif CX3CX2C. Catalyses the final step in the de-novo biosynthesis of the lipoyl cofactor, which is the insertion of two sulfur atoms into an eight-carbon saturated fatty-acyl chain at C-6 and C-8. The lipoyl cofactor is essential for the function of several 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) [2,5]. The reaction starts by using an electron from the reduced form of the enzyme's [4Fe-4S] cluster to split AdoMet into methionine and a 5'-deoxyadenosyl radical. The high-energy 5'-deoxyadenosyl radical then initiates catalysis by abstracting a key hydrogen atom from the relevant substrate [1]. The sulfur atoms are inserted with inversion of configuration [4]. The other enzymes involved in the biosynthesis of lipoyl cofactor are EC 2.3.1.181, lipoyl(octanoyl) transferase and EC 2.7.7.63, lipoate—protein ligase.

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. [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. [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. [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. [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. [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. [PMID: 11106496]

[EC 2.8.1.8 created 2006]


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