Enzyme Nomenclature

Continued from EC 6.2.1

EC 6.3

Forming Carbon—Nitrogen Bonds

Sections

EC 6.3.1 Acid—Ammonia (or Amine) Ligases (Amide Synthases)
EC 6.3.2 Acid—Amino-Acid Ligases (Peptide Synthases)
EC 6.3.3 Cyclo-Ligases
EC 6.3.4 Other Carbon—Nitrogen Ligases
EC 6.3.5 Carbon—Nitrogen Ligases with Glutamine as Amido-N-Donor


EC 6.3.1 Acid—Ammonia (or Amine) Ligases (Amide Synthases)

Contents

EC 6.3.1.1 aspartate—ammonia ligase
EC 6.3.1.2 glutamine synthetase
EC 6.3.1.3 now EC 6.3.4.13
EC 6.3.1.4 aspartate—ammonia ligase (ADP-forming)
EC 6.3.1.5 NAD+ synthase
EC 6.3.1.6 glutamate—ethylamine ligase
EC 6.3.1.7 4-methyleneglutamate—ammonia ligase
EC 6.3.1.8 glutathionylspermidine synthase
EC 6.3.1.9 trypanothione synthase
EC 6.3.1.10 adenosylcobinamide-phosphate synthase
EC 6.3.1.11 glutamate—putrescine ligase
EC 6.3.1.12 D-aspartate ligase)
EC 6.3.1.13 L-cysteine:1D-myo-inositol 2-amino-2-deoxy-α-D-glucopyranoside ligase
EC 6.3.1.14 diphthine—ammonia ligase
EC 6.3.1.15 8-demethylnovobiocic acid synthase
EC 6.3.1.16 transferred, misclassified, see EC 6.3.3.6
EC 6.3.1.17 β-citrylglutamate synthase
EC 6.3.1.18 γ-glutamylanilide synthase
EC 6.3.1.19 prokaryotic ubiquitin-like protein ligase

EC 6.3.1.20 lipoate—protein ligase

Entries

EC 6.3.1.1

Accepted name: aspartate—ammonia ligase

Reaction: ATP + L-aspartate + NH3 = AMP + diphosphate + L-asparagine

Other name(s): asparagine synthetase; L-asparagine synthetase

Systematic name: L-aspartate:ammonia ligase (AMP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-69-2

References:

1. Ravel, J.M., Norton, S.J., Humphreys, J.S. and Shive, W. Asparagine biosynthesis in Lactobacillus arabinosus and its control by asparagine through enzyme inhibition and repression. J. Biol. Chem. 237 (1962) 2845-2849.

2. Webster, G.C. and Varner, J.E. Aspartate metabolism and asparagine synthesis in plant systems. J. Biol. Chem. 215 (1955) 91-99.

[EC 6.3.1.1 created 1961]

EC 6.3.1.2

Accepted name: glutamine synthetase

Reaction: ATP + L-glutamate + NH3 = ADP + phosphate + L-glutamine

Other name(s): glutamate—ammonia ligase; glutamylhydroxamic synthetase; L-glutamine synthetase; GS

Systematic name: L-glutamate:ammonia ligase (ADP-forming)

Comments: Glutamine synthetase, which catalyses the incorporation of ammonium into glutamate, is a key enzyme of nitrogen metabolism found in all domains of life. Several types have been described, differing in their oligomeric structures and cofactor requirements.

Links to other databases: BRENDA, EXPASY, GTD, KEGG, MetaCyc, PDB, CAS registry number: 9023-70-5

References:

1. Elliott, W.H. Isolation of glutamine synthetase and glutamotransferase from green peas. J. Biol. Chem. 201 (1953) 661-672. [PMID: 13061404]

2. Fry, B.A. Glutamine synthesis by Micrococcus pyogenes var. aureus. Biochem. J. 59 (1955) 579-589. [PMID: 14363150]

3. Lajtha, A., Mela, P. and Waelsch, H. Manganese-dependent glutamotransferase. J. Biol. Chem. 205 (1953) 553-564. [PMID: 13129232]

4. Meister, A. Glutamine synthesis. In: Boyer, P.D., Lardy, H. and Myrbäck, K. (Eds), The Enzymes, 2nd edn, vol. 6, Academic Press, New York, 1962, pp. 443-468.

5. Woolfolk, C.A., Shapiro, B. and Stadtman, E.R. Regulation of glutamine synthetase. I. Purification and properties of glutamine synthetase from Escherichia coli. Arch. Biochem. Biophys. 116 (1966) 177-192. [PMID: 5336023]

6. Kumada, Y., Benson, D.R., Hillemann, D., Hosted, T.J., Rochefort, D.A., Thompson, C.J., Wohlleben, W. and Tateno, Y. Evolution of the glutamine synthetase gene, one of the oldest existing and functioning genes. Proc. Natl. Acad. Sci. USA 90 (1993) 3009-3013. [PMID: 8096645]

7. Llorca, O., Betti, M., Gonzalez, J.M., Valencia, A., Marquez, A.J. and Valpuesta, J.M. The three-dimensional structure of an eukaryotic glutamine synthetase: functional implications of its oligomeric structure. J. Struct. Biol. 156 (2006) 469-479. [PMID: 16884924]

8. Martinez-Espinosa, R.M., Esclapez, J., Bautista, V. and Bonete, M.J. An octameric prokaryotic glutamine synthetase from the haloarchaeon Haloferax mediterranei. FEMS Microbiol. Lett. 264 (2006) 110-116. [PMID: 17020556]

[EC 6.3.1.2 created 1961, modified 2016]

[EC 6.3.1.3 Transferred entry: now EC 6.3.4.13 phosphoribosylamine—glycine ligase (created 1961, deleted 1972)]

EC 6.3.1.4

Accepted name: aspartate—ammonia ligase (ADP-forming)

Reaction: ATP + L-aspartate + NH3 = ADP + phosphate + L-asparagine

Other name(s): asparagine synthetase (ADP-forming); asparagine synthetase (adenosine diphosphate-forming)

Systematic name: L-aspartate:ammonia ligase (ADP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 37318-61-9

References:

1. Nair, P.M. Asparagine synthetase from γ-irradiated potatoes. Arch. Biochem. Biophys. 133 (1969) 208-215. [PMID: 5820987]

[EC 6.3.1.4 created 1972]

EC 6.3.1.5

Accepted name: NAD+ synthase

Reaction: ATP + deamido-NAD+ + NH3 = AMP + diphosphate + NAD+

Other name(s): NAD synthetase; NAD synthase; nicotinamide adenine dinucleotide synthetase; diphosphopyridine nucleotide synthetase

Systematic name: deamido-NAD+:ammonia ligase (AMP-forming)

Comments: L-Glutamine also acts, more slowly, as amido-donor [cf. EC 6.3.5.1, NAD+ synthase (glutamine-hydrolysing)].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9032-69-3

References:

1. Spencer, R.L. and Preiss, J. Biosynthesis of diphosphopyridine nucleotide. The purification and the properties of diphosphopyridine nucleotide synthetase from Escherichia coli B. J. Biol. Chem. 242 (1967) 385-392. [PMID: 4290215]

[EC 6.3.1.5 created 1972]

EC 6.3.1.6

Accepted name: glutamate—ethylamine ligase

Reaction: ATP + L-glutamate + ethylamine = ADP + phosphate + N5-ethyl-L-glutamine

Other name(s): N5-ethyl-L-glutamine synthetase; theanine synthetase; N5-ethylglutamine synthetase

Systematic name: L-glutamate:ethylamine ligase (ADP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 62213-31-4

References:

1. Sasaoka, K. and Kito, M. Synthesis of theanine by tea seedling homogenate. Agric. Biol. Chem. 28 (1964) 313-317.

2. Sasaoka, K., Kito, M. and Inagaki, H. Studies on the biosynthesis of theanine in tea seedlings. Synthesis of theanine by the homogenate of tea seedlings. Agric. Biol. Chem. 27 (1963) 467-468.

3. Sasaoka, K., Kito, M. and Onishi, Y. Some properties of the theanine synthesizing enzyme in tea seedlings. Agric. Biol. Chem. 29 (1965) 984-988.

[EC 6.3.1.6 created 1976]

EC 6.3.1.7

Accepted name: 4-methyleneglutamate—ammonia ligase

Reaction: ATP + 4-methylene-L-glutamate + NH3 = AMP + diphosphate + 4-methylene-L-glutamine

Other name(s): 4-methyleneglutamine synthetase

Systematic name: 4-methylene-L-glutamate:ammonia ligase (AMP-forming)

Comments: Glutamine can act instead of NH3, but more slowly.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 85537-85-5

References:

1. Winter, H.C., Su, T.-Z. and Dekker, E.E. 4-Methyleneglutamine synthetase: a new amide synthetase present in germinating peanuts. Biochem. Biophys. Res. Commun. 111 (1983) 484-489. [PMID: 6838571]

[EC 6.3.1.7 created 1986]

EC 6.3.1.8

Accepted name: glutathionylspermidine synthase

Reaction: glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

For diagram click here.

Glossary: glutathione = γ-L-glutamyl-L-cysteinyl-glycine
spermidine

Other name(s): glutathione:spermidine ligase (ADP-forming)

Systematic name: γ-L-Glutamyl-L-cysteinyl-glycine:spermidine ligase (ADP-forming) [spermidine is numbered so that atom N-1 is in the amino group of the aminopropyl part of the molecule]

Comments: Requires magnesium ions. Involved in the synthesis of trypanothione in trypanosomatids. The enzyme from Escherichia coli is bifunctional and also catalyses the glutathionylspermidine amidase (EC 3.5.1.78) reaction, resulting in a net hydrolysis of ATP.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9077-09-2

References:

1. Smith, K., Nadeau, K., Bradley, M., Walsh, C.T., Fairlamb, A.H. Purification of glutathionylspermidine and trypanothione synthase from Crithidia fasciculata. Protein Sci. 1 (1992) 874-883. [PMID: 1304372]

2. Bollinger, J.M., Kwon, D.S., Huisman, G.W., Kolter, R., Walsh, C.T. Glutathionylspermidine metabolism in E. coli. Purification, cloning, overproduction and characterization of a bifunctional glutathionyl spermidine synthetase/amidase. J. Biol. Chem. 270 (1995) 14031-14041. [PMID: 7775463]

[EC 6.3.1.8 created 1999]

EC 6.3.1.9

Accepted name: trypanothione synthase

Reaction: (1) glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
(2) glutathione + glutathionylspermidine + ATP = N1,N8-bis(glutathionyl)spermidine + ADP + phosphate

For diagram of reaction click here.

Glossary: N1,N8-bis(glutathionyl)spermidine = trypanothione

Other name(s): glutathionylspermidine:glutathione ligase (ADP-forming)

Systematic name: spermidine/glutathionylspermidine:glutathione ligase (ADP-forming)

Comments: The enzyme, characterized from several trypanosomatids (e.g. Trypanosoma cruzi) catalyses two subsequent reactions, leading to production of trypanothione from glutathione and spermidine. Some trypanosomatids (e.g. Crithidia species and some Leishmania species) also contain an enzyme that only carries out the first reaction (cf. EC 6.3.1.8, glutathionylspermidine synthase). The enzyme is bifunctional, and also catalyses the hydrolysis of glutathionylspermidine and trypanothione (cf. EC 3.5.1.78, glutathionylspermidine amidase).

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number: 130246-69-4

References:

1. Smith, K., Nadeau, K., Bradley, M., Walsh, C.T., Fairlamb, A.H. Purification of glutathionylspermidine and trypanothione synthase from Crithidia fasciculata. Protein Sci. 1 (1992) 874-883. [PMID: 1304372]

2. Oza, S.L., Tetaud, E., Ariyanayagam, M.R., Warnon, S.S. and Fairlamb, A.H. A single enzyme catalyses formation of trypanothione from glutathione and spermidine in Trypanosoma cruzi. J. Biol. Chem. 277 (2002) 35853-35861. [PMID: 12121990]

3. Comini, M., Menge, U., Wissing, J. and Flohe, L. Trypanothione synthesis in crithidia revisited. J. Biol. Chem. 280 (2005) 6850-6860. [PMID: 15537651]

4. Oza, S.L., Shaw, M.P., Wyllie, S. and Fairlamb, A.H. Trypanothione biosynthesis in Leishmania major. Mol. Biochem. Parasitol. 139 (2005) 107-116. [PMID: 15610825]

5. Fyfe, P.K., Oza, S.L., Fairlamb, A.H. and Hunter, W.N. Leishmania trypanothione synthetase-amidase structure reveals a basis for regulation of conflicting synthetic and hydrolytic activities. J. Biol. Chem. 283 (2008) 17672-17680. [PMID: 18420578]

[EC 6.3.1.9 created 1999, modified 2014]

EC 6.3.1.10

Accepted name: adenosylcobinamide-phosphate synthase

Reaction: (1) ATP + adenosylcobyric acid + (R)-1-aminopropan-2-yl phosphate = ADP + phosphate + adenosylcobinamide phosphate

(2) ATP + adenosylcobyric acid + (R)-1-aminopropan-2-ol = ADP + phosphate + adenosylcobinamide

For diagram click here.

Other name(s): CbiB

Systematic name: adenosylcobyric acid:(R)-1-aminopropan-2-yl phosphate ligase (ADP-forming)

Comments: One of the substrates for this reaction, (R)-1-aminopropan-2-yl phosphate, is produced by CobD (EC 4.1.1.81, threonine-phosphate decarboxylase).

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 905988-16-1

References:

1. Cheong, C.G., Bauer, C.B., Brushaber, K.R., Escalante-Semerena, J.C. and Rayment, I. Three-dimensional structure of the L-threonine-O-3-phosphate decarboxylase (CobD) enzyme from Salmonella enterica. Biochemistry 41 (2002) 4798-4808. [PMID: 11939774]

2. Warren, M.J., Raux, E., Schubert, H.L. and Escalante-Semerena, J.C. The biosynthesis of adenosylcobalamin (vitamin B12). Nat. Prod. Rep. 19 (2002) 390-412. [PMID: 12195810]

[EC 6.3.1.10 created 2004]

EC 6.3.1.11

Accepted name: glutamate—putrescine ligase

Reaction: ATP + L-glutamate + putrescine = ADP + phosphate + γ-L-glutamylputrescine

Other name(s): γ-glutamylputrescine synthetase; YcjK

Systematic name: L-glutamate:putrescine ligase (ADP-forming)

Comments: Forms part of a novel bacterial putrescine utilization pathway in Escherichia coli.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 914090-78-1

References:

1. Kurihara, S., Oda, S., Kato, K., Kim, H.G., Koyanagi, T., Kumagai, H. and Suzuki, H. A novel putrescine utilization pathway involves γ-glutamylated intermediates of Escherichia coli K-12. J. Biol. Chem. 280 (2005) 4602-4608. [PMID: 15590624]

[EC 6.3.1.11 created 2005]

EC 6.3.1.12

Accepted name: D-aspartate ligase

Reaction: ATP + D-aspartate + [β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala)]n = [β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-6-N-(β-D-Asp)-L-Lys-D-Ala-D-Ala)]n + ADP + phosphate

For diagram click here.

Other name(s): Aslfm; UDP-MurNAc-pentapeptide:D-aspartate ligase; D-aspartic acid-activating enzyme

Systematic name: D-aspartate:[β-GlcNAc-(1→4)-Mur2Ac(oyl-L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala)]n ligase (ADP-forming)

Comments: This enzyme forms part of the peptidoglycan assembly pathway of Gram-positive bacteria grown in medium containing D-Asp. Normally, the side chains the acylate the 6-amino group of the L-lysine residue contain L-Ala-L-Ala but these amino acids are replaced by D-Asp when D-Asp is included in the medium. Hybrid chains containing L-Ala-D-Asp, L-Ala-L-Ala-D-Asp or D-Asp-L-Ala are not formed [4]. The enzyme belongs in the ATP-grasp protein superfamily [3,4]. The enzyme is highly specific for D-aspartate, as L-aspartate, D-glutamate, D-alanine, D-iso-asparagine and D-malic acid are not substrates [4]. In Enterococcus faecium, the substrate D-aspartate is produced by EC 5.1.1.13, aspartate racemase [4]

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Staudenbauer, W. and Strominger, J.L. Activation of D-aspartic acid for incorporation into peptidoglycan. J. Biol. Chem. 247 (1972) 5095-5102. [PMID: 4262567]

2. Staudenbauer, W., Willoughby, E. and Strominger, J.L. Further studies of the D-aspartic acid-activating enzyme of Streptococcus faecalis and its attachment to the membrane. J. Biol. Chem. 247 (1972) 5289-5296. [PMID: 4626717]

3. Galperin, M.Y. and Koonin, E.V. A diverse superfamily of enzymes with ATP-dependent carboxylate-amine/thiol ligase activity. Protein Sci. 6 (1997) 2639-2643. [PMID: 9416615]

4. Bellais, S., Arthur, M., Dubost, L., Hugonnet, J.E., Gutmann, L., van Heijenoort, J., Legrand, R., Brouard, J.P., Rice, L. and Mainardi, J.L. Aslfm, the D-aspartate ligase responsible for the addition of D-aspartic acid onto the peptidoglycan precursor of Enterococcus faecium. J. Biol. Chem. 281 (2006) 11586-11594. [PMID: 16510449]

[EC 6.3.1.12 created 2006]

EC 6.3.1.13

Accepted name: L-cysteine:1D-myo-inositol 2-amino-2-deoxy-α-D-glucopyranoside ligase

Reaction: 1-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-1D-myo-inositol + L-cysteine + ATP = 1-O-[2-(L-cysteinamido)-2-deoxy-α-D-glucopyranosyl]-1D-myo-inositol + AMP + diphosphate

Glossary: mycothiol = 1-O-[2-(N2-acetyl-L-cysteinamido)-2-deoxy--D-glucopyranosyl]-1D-myo-inositol

Other name(s): MshC; MshC ligase; Cys:GlcN-Ins ligase; mycothiol ligase

Systematic name: L-cysteine:1-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-1D-myo-inositol ligase (AMP-forming)

Comments: This enzyme is a key enzyme in the biosynthesis of mycothiol, a small molecular weight thiol found in Mycobacteria spp. and other actinomycetes. Mycothiol plays a fundamental role in these organisms by helping to provide protection from the effects of reactive oxygen species and electrophiles, including many antibiotics. The enzyme may represent a novel target for new classes of antituberculars [2]

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Fan, F., Luxenburger, A., Painter, G.F. and Blanchard, J.S. Steady-state and pre-steady-state kinetic analysis of Mycobacterium smegmatis cysteine ligase (MshC). Biochemistry 46 (2007) 11421-11429. [PMID: 17848100]

2. Gutierrez-Lugo, M.T., Newton, G.L., Fahey, R.C. and Bewley, C.A. Cloning, expression and rapid purification of active recombinant mycothiol ligase as B1 immunoglobulin binding domain of streptococcal protein G, glutathione-S-transferase and maltose binding protein fusion proteins in Mycobacterium smegmatis. Protein Expr. Purif. 50 (2006) 128-136. [PMID: 16908186]

3. Tremblay, L.W., Fan, F., Vetting, M.W. and Blanchard, J.S. The 1.6 Å crystal structure of Mycobacterium smegmatis MshC: the penultimate enzyme in the mycothiol biosynthetic pathway. Biochemistry 47 (2008) 13326-13335. [PMID: 19053270]

[EC 6.3.1.13 created 2009]

EC 6.3.1.14

Accepted name: diphthine—ammonia ligase

Reaction: ATP + diphthine-[translation elongation factor 2] + NH3 = AMP + diphosphate + diphthamide-[translation elongation factor 2]

For diagram of reaction click here.

Glossary: translation elongation factor 2 = EF2 = eEF2
diphthine = 2-[(3S)-3-carboxy-3-(trimethylammonio)propyl]-L-histidine
diphthamide =2-[(3S)-3-carbamoyl-3-(trimethylammonio)propyl]-L-histidine

Other name(s): diphthamide synthase; diphthamide synthetase; DPH6 (gene name); ATPBD4 (gene name)

Systematic name: diphthine-[translation elongation factor 2]:ammonia ligase (AMP-forming)

Comments: This amidase catalyses the last step in the conversion of an L-histidine residue in the translation elongation factor EF2 to diphthamide. This factor is found in all archaebacteria and eukaryotes, but not in eubacteria, and is the target of bacterial toxins such as the diphtheria toxin and the Pseudomonas exotoxin A (see EC 2.4.2.36, NAD+—diphthamide ADP-ribosyltransferase). The substrate of the enzyme, diphthine, is produced by EC 2.1.1.98, diphthine synthase.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 114514-33-9

References:

1. Moehring, T.J. and Moehring, J.M. Mutant cultured cells used to study the synthesis of diphthamide. UCLA Symp. Mol. Cell. Biol. New Ser. 45 (1987) 53-63.

2. Moehring, J.M. and Moehring, T.J. The post-translational trimethylation of diphthamide studied in vitro. J. Biol. Chem. 263 (1988) 3840-3844. [PMID: 3346227]

3. Su, X., Lin, Z., Chen, W., Jiang, H., Zhang, S. and Lin, H. Chemogenomic approach identified yeast YLR143W as diphthamide synthetase. Proc. Natl. Acad. Sci. USA 109 (2012) 19983-19987. [PMID: 23169644]

[EC 6.3.1.14 created 1990 as EC 6.3.2.22, transferred 2010 to EC 6.3.1.14, modified 2013]

EC 6.3.1.15

Accepted name: 8-demethylnovobiocic acid synthase

Reaction: ATP + 3-dimethylallyl-4-hydroxybenzoate + 3-amino-4,7-dihydroxycoumarin = AMP + diphosphate + 8-demethylnovobiocic acid

For diagram of reaction click here.

Glossary: 8-demethylnovobiocic acid = N-(2,7-dihydroxy-4-oxochromen-3-yl)-4-hydroxy-3-(3-methylbut-2-enyl)benzamide

Other name(s): novL (gene name); novobiocin ligase; novobiocic acid synthetase (misleading); 8-desmethyl-novobiocic acid synthetase; 8-demethylnovobiocic acid synthetase

Systematic name: 3-dimethylallyl-4-hydroxybenzoate:3-amino-4,7-dihydroxycoumarin ligase (AMP-forming)

Comments: The enzyme is involved in the biosynthesis of the aminocoumarin antibiotic novobiocin.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Steffensky, M., Li, S.M. and Heide, L. Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides NCIMB 11891. J. Biol. Chem. 275 (2000) 21754-21760. [PMID: 10801869]

2. Pi, N., Meyers, C.L., Pacholec, M., Walsh, C.T. and Leary, J.A. Mass spectrometric characterization of a three-enzyme tandem reaction for assembly and modification of the novobiocin skeleton. Proc. Natl. Acad. Sci. USA 101 (2004) 10036-10041. [PMID: 15218104]

3. Pacholec, M., Tao, J. and Walsh, C.T. CouO and NovO: C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis. Biochemistry 44 (2005) 14969-14976. [PMID: 16274243]

[EC 6.3.1.15 created 2013]

[EC 6.3.1.16 Transferred entry: carbapenam-3-carboxylate synthetase. The enzyme was discovered at the public-review stage to have been misclassified and so was withdrawn. See EC 6.3.3.6, carbapenam-3-carboxylate synthase (EC 6.3.1.16 created 2013, deleted 2013)]

EC 6.3.1.17

Accepted name: β-citrylglutamate synthase

Reaction: ATP + citrate + L-glutamate = ADP + phosphate + β-citryl-L-glutamate

Other name(s): NAAG synthetase I; NAAGS-I; RIMKLB (gene name) (ambiguous)

Systematic name: citrate:L-glutamate ligase (ADP-forming)

Comments: The enzyme, found in animals, also has the activity of EC 6.3.2.41, N-acetylaspartylglutamate synthase.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Collard, F., Stroobant, V., Lamosa, P., Kapanda, C.N., Lambert, D.M., Muccioli, G.G., Poupaert, J.H., Opperdoes, F. and Van Schaftingen, E. Molecular identification of N-acetylaspartylglutamate synthase and β-citrylglutamate synthase. J. Biol. Chem. 285 (2010) 29826-29833. [PMID: 20657015]

[EC 6.3.1.17 created 2014]

EC 6.3.1.18

Accepted name: γ-glutamylanilide synthase

Reaction: ATP + L-glutamate + aniline = ADP + phosphate + N5-phenyl-L-glutamine

Glossary: γ-glutamylanilide = N5-phenyl-L-glutamine

Other name(s): atdA1 (gene name); tdnQ (gene name); dcaQ (gene name)

Systematic name: L-glutamate:aniline ligase (ADP-forming)

Comments: Requires Mg2+. The enzyme, characterized from the bacterium Acinetobacter sp. YAA, catalyses the first step in the degradation of aniline. It can also accept chlorinated and methylated forms of aniline, preferrably in the o- and p-positions.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Takeo, M., Ohara, A., Sakae, S., Okamoto, Y., Kitamura, C., Kato, D. and Negoro, S. Function of a glutamine synthetase-like protein in bacterial aniline oxidation via γ-glutamylanilide. J. Bacteriol. 195 (2013) 4406-4414. [PMID: 23893114]

[EC 6.3.1.18 created 2014]

EC 6.3.1.19

Accepted name: prokaryotic ubiquitin-like protein ligase

Reaction: ATP + [prokaryotic ubiquitin-like protein]-L-glutamate + [protein]-L-lysine = ADP + phosphate + N6-([prokaryotic ubiquitin-like protein]-γ-L-glutamyl)-[protein]-L-lysine

Other name(s): PafA (ambiguous); Pup ligase; proteasome accessory factor A

Systematic name: [prokaryotic ubiquitin-like protein]:[protein]-L-lysine

Comments: The enzyme has been characterized from the bacteria Mycobacterium tuberculosis and Corynebacterium glutamicum. It catalyses the ligation of the prokaryotic ubiquitin-like protein (Pup) to a target protein by forming a bond between an ε-amino group of a lysine residue of the target protein and the γ-carboxylate of the C-terminal glutamate of the ubiquitin-like protein (Pup). The attachment of Pup, also known as Pupylation, marks proteins for proteasomal degradation.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Sutter, M., Damberger, F.F., Imkamp, F., Allain, F.H. and Weber-Ban, E. Prokaryotic ubiquitin-like protein (Pup) is coupled to substrates via the side chain of its C-terminal glutamate. J. Am. Chem. Soc. 132 (2010) 5610-5612. [PMID: 20355727]

2. Guth, E., Thommen, M. and Weber-Ban, E. Mycobacterial ubiquitin-like protein ligase PafA follows a two-step reaction pathway with a phosphorylated pup intermediate. J. Biol. Chem. 286 (2011) 4412-4419. [PMID: 21081505]

3. Ofer, N., Forer, N., Korman, M., Vishkautzan, M., Khalaila, I. and Gur, E. Allosteric transitions direct protein tagging by PafA, the prokaryotic ubiquitin-like protein (Pup) ligase. J. Biol. Chem. 288 (2013) 11287-11293. [PMID: 23471967]

4. Barandun, J., Delley, C.L., Ban, N. and Weber-Ban, E. Crystal structure of the complex between prokaryotic ubiquitin-like protein and its ligase PafA. J. Am. Chem. Soc. 135 (2013) 6794-6797. [PMID: 23601177]

5. Striebel, F., Imkamp, F., Özcelik, D. and Weber-Ban, E. Pupylation as a signal for proteasomal degradation in bacteria. Biochim. Biophys. Acta 1843 (2014) 103-113. [PMID: 23557784]

[EC 6.3.1.19 created 2015]

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, CAS registry number:

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. [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. [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. [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. [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. [PMID: 10966480]

[EC 6.3.1.20 created 2006 as EC 2.7.7.63, transferred 2016 to EC 6.3.1.20]


EC 6.3.2 Acid—Amino-Acid Ligases (Peptide Synthases)

Contents

EC 6.3.2.1 pantoate—β-alanine ligase (AMP-forming)
EC 6.3.2.2 glutamate—cysteine ligase
EC 6.3.2.3 glutathione synthase
EC 6.3.2.4 D-alanine—D-alanine ligase
EC 6.3.2.5 phosphopantothenate—cysteine ligase (CTP)
EC 6.3.2.6 phosphoribosylaminoimidazolesuccinocarboxamide synthase
EC 6.3.2.7 UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase
EC 6.3.2.8 UDP-N-acetylmuramate—L-alanine ligase
EC 6.3.2.9 UDP-N-acetylmuramoylalanine—D-glutamate ligase
EC 6.3.2.10 UDP-N-acetylmuramoylalanyl-tripeptide—D-alanyl-D-alanine ligase
EC 6.3.2.11 carnosine synthase
EC 6.3.2.12 dihydrofolate synthase
EC 6.3.2.13 UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—2,6-diaminopimelate ligase
EC 6.3.2.14 enterobactin synthase
EC 6.3.2.15 deleted, due to EC 6.3.2.10
EC 6.3.2.16 D-alanine—alanyl-poly(glycerolphosphate) ligase
EC 6.3.2.17 tetrahydrofolate synthase
EC 6.3.2.18 γ-glutamylhistamine synthase
EC 6.3.2.19 deleted now covered by EC 6.2.1.45, EC 2.3.2.23 and EC 2.3.2.27
EC 6.3.2.20 indoleacetate—lysine synthetase
EC 6.3.2.21 deleted now covered by EC 6.2.1.45 and EC 2.3.2.27
EC 6.3.2.22 deleted now EC 6.3.1.14
EC 6.3.2.23 homoglutathione synthase
EC 6.3.2.24 tyrosine—arginine ligase
EC 6.3.2.25 tubulin—tyrosine ligase
EC 6.3.2.26 N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase
EC 6.3.2.27 deleted now covered by EC 6.3.2.38 and EC 6.3.2.39
EC 6.3.2.28 transferred now EC 6.3.2.49
EC 6.3.2.29 cyanophycin synthase (L-aspartate-adding)
EC 6.3.2.30 cyanophycin synthase (L-arginine-adding)
EC 6.3.2.31 coenzyme F420-0:L-glutamate ligase
EC 6.3.2.32 coenzyme γ-F420-2:α-L-glutamate ligase
EC 6.3.2.33 tetrahydrosarcinapterin synthase
EC 6.3.2.34 coenzyme F420-1:γ-L-glutamate ligase
EC 6.3.2.35 D-alanine—D-serine ligase
EC 6.3.2.36 4-phosphopantoate-β-alanine ligase

EC 6.3.2.37 UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—D-lysine ligase
EC 6.3.2.38 N2-citryl-N6-acetyl-N6-hydroxylysine synthase
EC 6.3.2.39 aerobactin synthase
EC 6.3.2.40 cyclopeptine synthase
EC 6.3.2.41 N-acetylaspartylglutamate synthase
EC 6.3.2.42 N-acetylaspartylglutamylglutamate synthase
EC 6.3.2.43 [lysine-biosynthesis-protein LysW]—L-2-aminoadipate ligase
EC 6.3.2.44 pantoate—β-alanine ligase (ADP-forming)
EC 6.3.2.45 UDP-N-acetylmuramate L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate ligase
EC 6.3.2.46 fumarate—(S)-2,3-diaminopropanoate ligase
EC 6.3.2.47 dapdiamide synthase
EC 6.3.2.48 L-arginine-specific L-amino acid ligase
EC 6.3.2.49 L-alanine-L-anticapsin ligase
EC 6.3.2.50 tenuazonic acid synthetase
EC 6.3.2.51 phosphopantothenate—cysteine ligase (ATP)

Entries

EC 6.3.2.1

Accepted name: pantoate—β-alanine ligase (AMP-forming)

Reaction: ATP + (R)-pantoate + β-alanine = AMP + diphosphate + (R)-pantothenate

For diagram of reaction click here.

Glossary: (R)-pantoate = (2R)-2,4-dihydroxy-3,3-dimethylbutanoate
(R)-pantothenate = 3-[(2R)-2,4-dihydroxy-3,3-dimethylbutanamido]propanoate

Other name(s): pantothenate synthetase; pantoate activating enzyme; pantoic-activating enzyme; D-pantoate:β-alanine ligase (AMP-forming); pantoate—β-alanine ligase (ambiguous)

Systematic name: (R)-pantoate:β-alanine ligase (AMP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9023-49-8

References:

1. Ginoza, H.S. and Altenbern, R.A. The pantothenate-synthesizing enzyme cell-free extracts of Brucella abortus, strain 19. Arch. Biochem. Biophys. 56 (1955) 537-541. [PMID: 14377603]

2. Maas, W.K. Pantothenate studies. III. Description of the extracted pantothenate-synthesizing enzyme of Escherichia coli. J. Biol. Chem. 198 (1952) 23-32. [PMID: 12999714]

3. Maas, W.K. Mechanism of the enzymatic synthesis of pantothenate from β-alanine and pantoate. Fed. Proc. 15 (1956) 305-306.

[EC 6.3.2.1 created 1961, modified 2014]

EC 6.3.2.2

Accepted name: glutamate—cysteine ligase

Reaction: ATP + L-glutamate + L-cysteine = ADP + phosphate + γ-L-glutamyl-L-cysteine

For diagram of reaction click here.

Other name(s): γ-glutamylcysteine synthetase; γ-glutamyl-L-cysteine synthetase; γ-glutamylcysteinyl synthetase

Systematic name: L-glutamate:L-cysteine γ-ligase (ADP-forming)

Comments: Can use L-aminohexanoate in place of glutamate.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-64-7

References:

1. Mackinnon, C.M., Carter, P.E., Smyth, S.J., Dunbar, B. and Fothergill, J.E. Molecular-cloning of cDNA for human-complement component c1s - the complete amino-acid sequence. Eur. J. Biochem. 169 (1987) 547-553.

2. Snoke, J.E., Yanari, S. and Bloch, K. Synthesis of glutathione from γ-glutamylcysteine. J. Biol. Chem. 201 (1953) 573-586.

3. Mandeles, S. and Bloch, K. Enzymatic synthesis of γ-glutamylcysteine. J. Biol. Chem. 214 (1955) 639-646.

[EC 6.3.2.2 created 1961]

EC 6.3.2.3

Accepted name: glutathione synthase

Reaction: ATP + γ-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione

For diagram of reaction click here.

Other name(s): glutathione synthetase; GSH synthetase

Systematic name: γ-L-glutamyl-L-cysteine:glycine ligase (ADP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-62-5

References:

1. Law, M.Y. and Halliwell, B. Purification and properties of glutathione synthetase from (Spinacia oleracea) leaves. Plant Sci. 43 (1986) 185-191.

2. Macnicol, P.K. Homoglutathione and glutathione synthetases of legume seedlings - partial-purification and substrate-specificity. Plant Sci. 53 (1987) 229-235.

[EC 6.3.2.3 created 1961]

EC 6.3.2.4

Accepted name: D-alanine—D-alanine ligase

Reaction: ATP + 2 D-alanine = ADP + phosphate + D-alanyl-D-alanine

For diagram click here.

Other name(s): MurE synthetase [ambiguous]; alanine:alanine ligase (ADP-forming); alanylalanine synthetase

Systematic name: D-alanine:D-alanine ligase (ADP-forming)

Comments: Involved with EC 6.3.2.7 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase) or EC 6.3.2.13 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—2,6-diaminopimelate ligase), EC 6.3.2.8 (UDP-N-acetylmuramate—L-alanine ligase), EC 6.3.2.9 (UDP-N-acetylmuramoyl-L-alanine—D-glutamate ligase) and EC 6.3.2.10 (UDP-N-acetylmuramoyl-tripeptide—D-alanyl-D-alanine ligase) in the synthesis of a cell-wall peptide (click here for diagram).

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-63-6

References:

1. Ito, E. and Strominger, J.L. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. II. Enzymatic synthesis and addition of D-alanyl-D-alanine. J. Biol. Chem. 237 (1962) 2696-2703.

2. Neuhaus, F.C. Kinetic studies on D-Ala-D-Ala synthetase. Fed. Proc. 21 (1962) 229 only.

3. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.4 created 1961, modified 2002]

EC 6.3.2.5

Accepted name: phosphopantothenate—cysteine ligase (CTP)

Reaction: CTP + (R)-4'-phosphopantothenate + L-cysteine = CMP + diphosphate + N-[(R)-4'-phosphopantothenoyl]-L-cysteine

For diagram of reaction click here.

Other name(s): phosphopantothenoylcysteine synthetase; phosphopantothenate—cysteine ligase

Systematic name: (R)-4'-phosphopantothenate:L-cysteine ligase

Comments: A key enzyme in the production of coenzyme A. The bacterial enzyme requires CTP, in contrast to the eukaryotic enzyme, EC 6.3.2.51, which requires ATP. Cysteine can be replaced by some of its derivatives.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, PDB, CAS registry number: 9023-50-1

References:

1. Brown, G.M. The metabolism of pantothenic acid. J. Biol. Chem. 234 (1959) 370-378. [PMID: 13630913]

2. Strauss, E., Kinsland, C., Ge, Y., McLafferty, F.W. and Begley, T.P. Phosphopantothenoylcysteine synthetase from Escherichia coli. Identification and characterization of the last unidentified Coenzyme A biosynthetic enzymes in bacteria. J. Biol. Chem. 276 (2001) 13513-13516. [PMID: 11278255]

3. Kupke, T. Molecular characterization of the 4'-phosphopantothenoylcysteine synthetase domain of bacterial Dfp flavoproteins. J. Biol. Chem. 277 (2002) 36137-36145. [PMID: 12140293]

[EC 6.3.2.5 created 1961, modified 2003, modified 2017]

EC 6.3.2.6

Accepted name: phosphoribosylaminoimidazolesuccinocarboxamide synthase

Reaction: ATP + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate + L-aspartate = ADP + phosphate + (S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate

For diagram, click here

Other name(s): phosphoribosylaminoimidazole-succinocarboxamide synthetase; PurC; SAICAR synthetase; 4-(N-succinocarboxamide)-5-aminoimidazole synthetase; 4-[(N-succinylamino)carbonyl]-5-aminoimidazole ribonucleotide synthetase; SAICARs; 5-aminoimidazole-4-N-succinocarboxamide ribonucleotide synthetase; phosphoribosylaminoimidazolesuccinocarboxamide synthetase; 5-aminoimidazole-4-N-succinocarboxamide ribonucleotide synthetase

Systematic name: 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate:L-aspartate ligase (ADP-forming)

Comments: Forms part of the purine biosynthesis pathway.

Links to other databases: BRENDA, EXPASY,KEGG, Metacyc, PDB, CAS registry number: 9023-67-0

References:

1. Lukens, L.N. and Buchanan, J.M. Biosynthesis of purines. XXIV. The enzymatic synthesis of 5-amino-1-ribosyl-4-imidazolecarboxylic acid 5'-phosphate from 5-amino-1-ribosylimidazole 5'-phosphate and carbon dioxide. J. Biol. Chem. 234 (1959) 1799-1805. [PMID: 13672967]

2. Parker, J. Identification of the purC gene product of Escherichia coli. J. Bacteriol. 157 (1984) 712-717. [PMID: 6365889]

3. Ebbole, D.J. and Zalkin, H. Cloning and characterization of a 12-gene cluster from Bacillus subtilis encoding nine enzymes for de novo purine nucleotide synthesis. J. Biol. Chem. 262 (1987) 8274-8287. [PMID: 3036807]

4. Chen, Z.D., Dixon, J.E. and Zalkin, H. Cloning of a chicken liver cDNA encoding 5-aminoimidazole ribonucleotide carboxylase and 5-aminoimidazole-4-N-succinocarboxamide ribonucleotide synthetase by functional complementation of Escherichia coli pur mutants. Proc. Natl. Acad. Sci. USA 87 (1990) 3097-3101. [PMID: 1691501]

5. O'Donnell, A.F., Tiong, S., Nash, D. and Clark, D.V. The Drosophila melanogaster ade5 gene encodes a bifunctional enzyme for two steps in the de novo purine synthesis pathway. Genetics 154 (2000) 1239-1253. [PMID: 10757766]

6. Nelson, S.W., Binkowski, D.J., Honzatko, R.B. and Fromm, H.J. Mechanism of action of Escherichia coli phosphoribosylaminoimidazolesuccinocarboxamide synthetase. Biochemistry 44 (2005) 766-774. [PMID: 15641804]

[EC 6.3.2.6 created 1961, modified 2000, modified 2006]

EC 6.3.2.7

Accepted name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase

Reaction: ATP + UDP-N-acetyl-α-D-muramoyl-L-alanyl-D-glutamate + L-lysine = ADP + phosphate + UDP-N-acetyl-α-D-muramoyl-L-alanyl-γ-D-glutamyl-L-lysine

For diagram click here.

Other name(s): MurE synthetase; UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-L-lysine synthetase; uridine diphospho-N-acetylmuramoylalanyl-D-glutamyllysine synthetase; UPD-MurNAc-L-Ala-D-Glu:L-Lys ligase

Systematic name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:L-lysine γ-ligase (ADP-forming)

Comments: Involved with EC 6.3.2.4 (D-alanine—D-alanine ligase), EC 6.3.2.8 (UDP-N-acetylmuramate—L-alanine ligase), EC 6.3.2.9 (UDP-N-acetylmuramoyl-L-alanine—D-glutamate ligase) and EC 6.3.2.10 (UDP-N-acetylmuramoyl-tripeptide—D-alanyl-D-alanine ligase) in the synthesis of a cell-wall peptide (click here for diagram). This enzyme adds lysine in some Gram-positive organisms; in others and in Gram-negative organisms EC 6.3.2.13 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—2,6-diaminopimelate ligase) adds 2,6-diaminopimelate instead.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-51-2

References:

1. Ito, E. and Strominger, J.L. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. I. Enzymatic addition of L-alanine, D-glutamic acid, and L-lysine. J. Biol. Chem. 237 (1962) 2689-2695.

2. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.7 created 1961, modified 2002]

EC 6.3.2.8

Accepted name: UDP-N-acetylmuramate—L-alanine ligase

Reaction: ATP + UDP-N-acetyl-α-D-muramate + L-alanine = ADP + phosphate + UDP-N-acetyl-α-D-muramoyl-L-alanine

For diagram click here.

Other name(s): MurC synthetase; UDP-N-acetylmuramoyl-L-alanine synthetase; uridine diphospho-N-acetylmuramoylalanine synthetase; UDP-N-acetylmuramoylalanine synthetase; L-alanine-adding enzyme; UDP-acetylmuramyl-L-alanine synthetase; UDPMurNAc-L-alanine synthetase; L-Ala ligase; uridine diphosphate N-acetylmuramate:L-alanine ligase; uridine 5'-diphosphate-N-acetylmuramyl-L-alanine synthetase; uridine-diphosphate-N-acetylmuramate:L-alanine ligase; UDP-MurNAc:L-alanine ligase; alanine-adding enzyme; UDP-N-acetylmuramyl:L-alanine ligase

Systematic name: UDP-N-acetylmuramate:L-alanine ligase (ADP-forming)

Comments: Involved in the synthesis of a cell-wall peptide in bacteria.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-52-3

References:

1. Ito, E. and Strominger, J.L. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. I. Enzymatic addition of L-alanine, D-glutamic acid, and L-lysine. J. Biol. Chem. 237 (1962) 2689-2695.

2. Nathenson, S.G., Strominger, J.L. and Ito, E. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. IV. Purification and properties of D-glutamic acid-adding enzyme. J. Biol. Chem. 239 (1964) 1773-1776.

3. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.8 created 1965, modified 2002]

EC 6.3.2.9

Accepted name: UDP-N-acetylmuramoyl-L-alanine—D-glutamate ligase

Reaction: ATP + UDP-N-acetyl-α-D-muramoyl-L-alanine + D-glutamate = ADP + phosphate + UDP-N-acetyl-α-D-muramoyl-L-alanyl-D-glutamate

For diagram click here.

Other name(s): MurD synthetase; UDP-N-acetylmuramoyl-L-alanyl-D-glutamate synthetase; uridine diphospho-N-acetylmuramoylalanyl-D-glutamate synthetase; D-glutamate-adding enzyme; D-glutamate ligase; UDP-Mur-NAC-L-Ala:D-Glu ligase; UDP-N-acetylmuramoyl-L-alanine:glutamate ligase (ADP-forming); UDP-N-acetylmuramoylalanine—D-glutamate ligase

Systematic name: UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (ADP-forming)

Comments: Involved in the synthesis of a cell-wall peptide in bacteria.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9023-59-0

References:

1. Ito, E. and Strominger, J.L. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. I. Enzymatic addition of L-alanine, D-glutamic acid, and L-lysine. J. Biol. Chem. 237 (1962) 2689-2695.

2. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.9 created 1965, modified 2002]

EC 6.3.2.10

Accepted name: UDP-N-acetylmuramoyl-tripeptide—D-alanyl-D-alanine ligase

Reaction: ATP + UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-L-lysine + D-alanyl-D-alanine = ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-L-lysyl-D-alanyl-D-alanine

For diagram click here.

Other name(s): MurF synthetase; UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-L-lysyl-D-alanyl-D-alanine synthetase; UDP-N-acetylmuramoylalanyl-D-glutamyl-lysine-D-alanyl-D-alanine ligase; uridine diphosphoacetylmuramoylpentapeptide synthetase; UDPacetylmuramoylpentapeptide synthetase; UDP-MurNAc-L-Ala-D-Glu-L-Lys:D-Ala-D-Ala ligase

Systematic name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-L-lysine:D-alanyl-D-alanine ligase (ADP-forming)

Comments: Involved with EC 6.3.2.4 (D-alanine—D-alanine ligase), EC 6.3.2.7 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase) or EC 6.3.2.13 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—2,6-diaminopimelate ligase), EC 6.3.2.8 (UDP-N-acetylmuramate—L-alanine ligase) and EC 6.3.2.9 (UDP-N-acetylmuramoyl-L-alanine—D-glutamate ligase) in the synthesis of a cell-wall peptide (click here for diagram). This enzyme also catalyses the reaction when the C-terminal residue of the tripeptide is meso-2,4-diaminoheptanedioate (acylated at its L-centre), linking the D-Ala-D-Ala to the carboxy group of the L-centre. This activity was previously attributed to EC 6.3.2.15, which has since been deleted.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 55354-36-4

References:

1. Ito, E. and Strominger, J.L. Enzymatic synthesis of the peptide in bacterial uridine nucleotides. II. Enzymatic synthesis and addition of D-alanyl-D-alanine. J. Biol. Chem. 237 (1962) 2696-2703.

2. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.10 created 1965, modified 2002]

EC 6.3.2.11

Accepted name: carnosine synthase

Reaction: ATP + L-histidine + β-alanine = ADP + phosphate + carnosine

Glossary: carnosine = N-β-alanyl-L-histidine

Other name(s): carnosine synthetase; carnosine-anserine synthetase; homocarnosine-carnosine synthetase; carnosine-homocarnosine synthetase; L-histidine:β-alanine ligase (AMP-forming) (incorrect)

Systematic name: L-histidine:β-alanine ligase (ADP-forming)

Comments: This enzyme was thought to form AMP [1,2], but studies with highly purified enzyme proved that it forms ADP [4]. Carnosine is a dipeptide that is present at high concentrations in skeletal muscle and the olfactory bulb of vertebrates [3]. It is also found in the skeletal muscle of some invertebrates. The enzyme can also catalyse the formation of homocarnosine from 4-aminobutanoate and L-histidine, with much lower activity [4].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 9023-61-4

References:

1. Kalyankar, G.D. and Meister, A. Enzymatic synthesis of carnosine and related β-alanyl and γ-aminobutyryl peptides. J. Biol. Chem. 234 (1959) 3210-3218. [PMID: 14404206]

2. Stenesh, J.J. and Winnick, T. Carnosine-anserine synthetase of muscle. 4. Partial purification of the enzyme and further studies of β-alanyl peptide synthesis. Biochem. J. 77 (1960) 575-581. [PMID: 16748858]

3. Crush, K.G. Carnosine and related substances in animal tissues. Comp. Biochem. Physiol. 34 (1970) 3-30. [PMID: 4988625]

4. Drozak, J., Veiga-da-Cunha, M., Vertommen, D., Stroobant, V. and Van Schaftingen, E. Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). J. Biol. Chem. 285 (2010) 9346-9356. [PMID: 20097752]

[EC 6.3.2.11 created 1965, modified 2010]

EC 6.3.2.12

Accepted name: dihydrofolate synthase

Reaction: ATP + 7,8-dihydropteroate + L-glutamate = ADP + phosphate + 7,8-dihydropteroylglutamate

For diagram of reaction click here.

Other name(s): dihydrofolate synthetase; 7,8-dihydrofolate synthetase; H2-folate synthetase; 7,8-dihydropteroate:L-glutamate ligase (ADP); dihydropteroate:L-glutamate ligase (ADP-forming); DHFS

Systematic name: 7,8-dihydropteroate:L-glutamate ligase (ADP-forming)

Comments: In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.17, tetrahydrofolate synthase [2], the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates. In contrast, the activities are located on separate proteins in most eukaryotes studied to date [3]. This enzyme is reponsible for attaching the first glutamate residue to dihydropteroate to form dihydrofolate and is present only in those organisms that have the ability to synthesize tetrahydrofolate de novo, e.g. plants, most bacteria, fungi and protozoa [3].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 37318-62-0

References:

1. Griffin, M.J. and Brown, G.M. The biosynthesis of folic acid. III. Enzymatic formation of dihydrofolic acid from dihydropteroic acid and of tetrahydropteroylpolyglutamic acid compounds from tetrahydrofolic acid. J. Biol. Chem. 239 (1964) 310-316. [PMID: 14114858]

2. Bognar, A.L., Osborne, C., Shane, B., Singer, S.C. and Ferone, R. Folylpoly-γ-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product. J. Biol. Chem. 260 (1985) 5625-5630. [PMID: 2985605]

3. Ravanel, S., Cherest, H., Jabrin, S., Grunwald, D., Surdin-Kerjan, Y., Douce, R. and Rébeillé, F. Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA 98 (2001) 15360-15365. [PMID: 11752472]

4. Cherest, H., Thomas, D. and Surdin-Kerjan, Y. Polyglutamylation of folate coenzymes is necessary for methionine biosynthesis and maintenance of intact mitochondrial genome in Saccharomyces cerevisiae. J. Biol. Chem. 275 (2000) 14056-14063. [PMID: 10799479]

5. Cossins, E.A. and Chen, L. Folates and one-carbon metabolism in plants and fungi. Phytochemistry 45 (1997) 437-452. [PMID: 9190084]

[EC 6.3.2.12 created 1972, modified 2005]

EC 6.3.2.13

Accepted name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—2,6-diaminopimelate ligase

Reaction: ATP + UDP-N-acetyl-α-D-muramoyl-L-alanyl-D-glutamate + meso-2,6-diaminoheptanedioate = ADP + phosphate + UDP-N-acetyl-α-D-muramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate

For diagram of reaction, click here.

Other name(s): MurE synthetase [ambiguous]; UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:meso-2,6-diamino-heptanedioate ligase (ADP-forming); UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelate synthetase; UDP-N-acetylmuramoylalanyl-D-glutamate—2,6-diaminopimelate ligase

Systematic name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:meso-2,6-diaminoheptanedioate γ-ligase (ADP-forming)

Comments: Involved in the synthesis of a cell-wall peptide in bacteria. This enzyme adds diaminopimelate in Gram-negative organisms and in some Gram-positive organisms; in others EC 6.3.2.7 (UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase) adds lysine instead. It is the amino group of the L-centre of the diaminopimelate that is acylated.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 9075-09-6

References:

1. Mizuno, Y. and Ito, E. Purification and properties of uridine diphosphate N-acetylmuramyl-L-alanyl-D-glutamate:meso-2,6-diaminopimelate ligase. J. Biol. Chem. 243 (1968) 2665-2672. [PMID: 4967958]

2. van Heijenoort, J. Recent advances in the formation of the bacterial peptidoglycan monomer unit. Nat. Prod. Rep. 18 (2001) 503-519. [PMID: 11699883]

[EC 6.3.2.13 created 1972, modified 2002, modified 2010]

EC 6.3.2.14

Accepted name: enterobactin synthase

Reaction: 6 ATP + 3 2,3-dihydroxybenzoate + 3 L-serine = enterobactin + 6 AMP + 6 diphosphate

For diagram of reaction click here.

Other name(s): N-(2,3-dihydroxybenzoyl)-serine synthetase; 2,3-dihydroxybenzoylserine synthetase; 2,3-dihydroxybenzoate—serine ligase

Systematic name: 2,3-dihydroxybenzoate:L-serine ligase

Comments: This enzyme complex catalyses the conversion of three molecules each of 2,3-dihydroxybenzoate and L-serine to form the siderophore enterobactin. In Escherichia coli the complex is formed by EntB (an aryl carrier protein that has to be activated by 4'-phosphopantetheine), EntD (a phosphopantetheinyl transferase that activates EntB), EntE (catalyses the ATP-dependent condensation of 2,3-dihydroxybenzoate and holo-EntB to form the covalently arylated form of EntB), and EntF (a four domain protein that catalyses the activation of L-serine by ATP, the condensation of the activated L-serine with the activated 2,3-dihydroxybenzoate, and the trimerization of three such moieties to a single enterobactin molecule).

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 37318-63-1

References:

1. Brot, N. and Goodwin, J. Regulation of 2,3-dihydroxybenzoylserine synthetase by iron. J. Biol. Chem. 243 (1968) 510-513. [PMID: 4966114]

2. Rusnak, F., Faraci, W.S. and Walsh, C.T. Subcloning, expression, and purification of the enterobactin biosynthetic enzyme 2,3-dihydroxybenzoate-AMP ligase: demonstration of enzyme-bound (2,3-dihydroxybenzoyl)adenylate product. Biochemistry 28 (1989) 6827-6835. [PMID: 2531000]

3. Rusnak, F., Liu, J., Quinn, N., Berchtold, G.A. and Walsh, C.T. Subcloning of the enterobactin biosynthetic gene entB: expression, purification, characterization, and substrate specificity of isochorismatase. Biochemistry 29 (1990) 1425-1435. [PMID: 2139796]

4. Rusnak, F., Sakaitani, M., Drueckhammer, D., Reichert, J. and Walsh, C.T. Biosynthesis of the Escherichia coli siderophore enterobactin: sequence of the entF gene, expression and purification of EntF, and analysis of covalent phosphopantetheine. Biochemistry 30 (1991) 2916-2927. [PMID: 1826089]

5. Gehring, A.M., Mori, I. and Walsh, C.T. Reconstitution and characterization of the Escherichia coli enterobactin synthetase from EntB, EntE, and EntF. Biochemistry 37 (1998) 2648-2659. [PMID: 9485415]

6. Shaw-Reid, C.A., Kelleher, N.L., Losey, H.C., Gehring, A.M., Berg, C. and Walsh, C.T. Assembly line enzymology by multimodular nonribosomal peptide synthetases: the thioesterase domain of E. coli EntF catalyzes both elongation and cyclolactonization. Chem. Biol. 6 (1999) 385-400. [PMID: 10375542]

[EC 6.3.2.14 created 1972, modified 2012]

[EC 6.3.2.15 Deleted entry: UDP-N-acetylmuramoylalanyl-D-glutamyl-2,6-diaminopimelate-D-alanyl-D-alanine ligase. The activity observed is due to EC 6.3.2.10, UDP-N-acetylmuramoyl-tripeptide—D-alanyl-D-alanine ligase. (EC 6.3.2.15 created 1976, deleted 2002)]

EC 6.3.2.16

Accepted name: D-alanine—alanyl-poly(glycerolphosphate) ligase

Reaction: ATP + D-alanine + alanyl-poly(glycerolphosphate) = ADP + phosphate + D-alanyl-alanyl-poly(glycerolphosphate)

Other name(s): D-alanyl-alanyl-poly(glycerolphosphate) synthetase; D-alanine:membrane-acceptor ligase; D-alanylalanylpoly(phosphoglycerol) synthetase; D-alanyl-poly(phosphoglycerol) synthetase; D-alanine-membrane acceptor-ligase

Systematic name: D-alanine:alanyl-poly(glycerolphosphate) ligase (ADP-forming)

Comments: Involved in the synthesis of teichoic acids.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 9046-58-6

References:

1. Reusch, V.M. and Neuhaus, F.C. D-Alanine: membrane acceptor ligase from Lactobacillus casei. J. Biol. Chem. 246 (1971) 6136-6143. [PMID: 4399593]

[EC 6.3.2.16 created 1976]

EC 6.3.2.17

Accepted name: tetrahydrofolate synthase

Reaction: ATP + tetrahydropteroyl-[γ-Glu]n + L-glutamate = ADP + phosphate + tetrahydropteroyl-[γ-Glu]n+1

For diagram click here.

Other name(s): folylpolyglutamate synthase; folate polyglutamate synthetase; formyltetrahydropteroyldiglutamate synthetase; N10-formyltetrahydropteroyldiglutamate synthetase; folylpoly-γ-glutamate synthase; folylpolyglutamyl synthetase; folylpoly(γ-glutamate) synthase; folylpolyglutamate synthetase; FPGS; tetrahydrofolylpolyglutamate synthase; tetrahydrofolate:L-glutamate γ-ligase (ADP-forming); tetrahydropteroyl-[γ-Glu]n:L-glutamate γ-ligase (ADP-forming)

Systematic name: tetrahydropteroyl-γ-polyglutamate:L-glutamate γ-ligase (ADP-forming)

Comments: In some bacteria, a single protein catalyses both this activity and that of EC 6.3.2.12, dihydrofolate synthase [3], the combined activity of which leads to the formation of the coenzyme polyglutamated tetrahydropteroate (H4PteGlun), i.e. various tetrahydrofolates (H4folate). In contrast, the activities are located on separate proteins in most eukaryotes studied to date [4]. In Arabidopsis thaliana, this enzyme is present as distinct isoforms in the mitochondria, the cytosol and the chloroplast. Each isoform is encoded by a separate gene, a situation that is unique among eukaryotes [4]. As the affinity of folate-dependent enzymes increases markedly with the number of glutamic residues, the tetrahydropteroyl polyglutamates are the preferred coenzymes of C1 metabolism. (reviewed in [5]). The enzymes from different sources (particularly eukaryotes versus prokaryotes) have different substrate specificities with regard to one-carbon substituents and the number of glutamate residues present on the tetrahydrofolates.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number: 63363-84-8

References:

1. Cichowicz, D., Foo, S.K. and Shane, B. Folylpoly-γ-glutamate synthesis by bacteria and mammalian cells. Mol. Cell. Biochem. 39 (1981) 209-228. [PMID: 6458762]

2. McGuire, J.J. and Bertino, J.R. Enzymatic synthesis and function of folylpolyglutamates. Mol. Cell. Biochem. 38 (1981) 19-48. [PMID: 7027025]

3. Bognar, A.L., Osborne, C., Shane, B., Singer, S.C. and Ferone, R. Folylpoly-γ-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product. J. Biol. Chem. 260 (1985) 5625-5630. [PMID: 2985605]

4. Ravanel, S., Cherest, H., Jabrin, S., Grunwald, D., Surdin-Kerjan, Y., Douce, R. and Rébeillé, F. Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana. Proc. Natl. Acad. Sci. USA 98 (2001) 15360-15365. [PMID: 11752472]

5. Cossins, E.A. and Chen, L. Folates and one-carbon metabolism in plants and fungi. Phytochemistry 45 (1997) 437-452. [PMID: 9190084]

6. Cherest, H., Thomas, D. and Surdin-Kerjan, Y. Polyglutamylation of folate coenzymes is necessary for methionine biosynthesis and maintenance of intact mitochondrial genome in Saccharomyces cerevisiae. J. Biol. Chem. 275 (2000) 14056-14063. [PMID: 10799479 ]

[EC 6.3.2.17 created 1984, modified 2003, modified 2005]

EC 6.3.2.18

Accepted name: γ-glutamylhistamine synthase

Reaction: ATP + L-glutamate + histamine = products of ATP breakdown + Nα-γ-L-glutamylhistamine

Other name(s): γ-glutaminylhistamine synthetase; γ-GHA synthetase

Systematic name: L-glutamate:histamine ligase

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 82904-08-3

References:

1. Stein, C. and Weinreich, D. An in vitro characterization of γ-glutamylhistamine synthetase: a novel enzyme catalyzing histamine metabolism in the central nervous system of the marine mollusk, Aplysia californica. J. Neurochem. 38 (1982) 204-214. [PMID: 6125565]

[EC 6.3.2.18 created 1986]

[EC 6.3.2.19 Deleted entry: ubiquitin—protein ligase. The ubiquitinylation process is now known to be performed by several enzymes in sequence, starting with EC 6.2.1.45 (ubiquitin-activating enzyme E1) and followed by several transfer reactions, including those of EC 2.3.2.23 (E2 ubiquitin-conjugating enzyme) and EC 2.3.2.27 (RING-type E3 ubiquitin transferase) (EC 6.3.2.19 created 1986, deleted 2015)]

EC 6.3.2.20

Accepted name: indoleacetate—lysine synthetase

Reaction: ATP + (indol-3-yl)acetate + L-lysine = ADP + phosphate + N6-[(indole-3-yl)acetyl]-L-lysine

Other name(s): indoleacetate:L-lysine ligase (ADP-forming)

Systematic name: (indol-3-yl)acetate:L-lysine ligase (ADP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 103537-15-1

References:

1. Glass, N.L. and Kosuge, T. Cloning of the gene for indoleacetic acid-lysine synthetase from Pseudomonas syringae subsp. savastanoi. J. Bacteriol. 166 (1986) 598. [PMID: 3084452]

2. Hutzinger, O. and Kosuge, T. Microbial synthesis and degradation of indole-3-acetic acid. 3. The isolation and characterization of indole-3-acetyl-ε-L-lysine. Biochemistry 7 (1968) 601-605. [PMID: 5644130]

[EC 6.3.2.20 created 1989]

[EC 6.3.2.21 Deleted entry: ubiquitin—calmodulin ligase. The reaction is performed by the sequential action of EC 6.2.1.45 (ubiquitin-activating enzyme E1), several ubiquitin transferases and finally by EC 2.3.2.27 [ubiquitin transferase RING E3 (calmodulin-selective)] (EC 6.3.2.21 created 1990, deleted 2015)]

[EC 6.3.2.22 Transferred entry: diphthine—ammonia ligase. Now EC 6.3.1.14, diphthine—ammonia ligase. (EC 6.3.2.22 created 1990, deleted 2010)]

EC 6.3.2.23

Accepted name: homoglutathione synthase

Reaction: ATP + γ-L-glutamyl-L-cysteine + β-alanine = ADP + phosphate + γ-L-glutamyl-L-cysteinyl-β-alanine

Other name(s): homoglutathione synthetase; β-alanine specific hGSH synthetase

Systematic name: γ-L-glutamyl-L-cysteine:β-alanine ligase (ADP-forming)

Comments: Not identical with EC 6.3.2.3 glutathione synthase.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 113875-72-2

References:

1. Macnicol, P.K. Homoglutathione and glutathione synthetases of legume seedlings - partial-purification and substrate-specificity. Plant Sci. 53 (1987) 229-235.

[EC 6.3.2.23 created 1990]

EC 6.3.2.24

Accepted name: tyrosine—arginine ligase

Reaction: ATP + L-tyrosine + L-arginine = AMP + diphosphate + L-tyrosyl-L-arginine

Other name(s): tyrosyl-arginine synthase; kyotorphin synthase; kyotorphin-synthesizing enzyme; kyotorphin synthetase

Systematic name: L-tyrosine:L-arginine ligase (AMP-forming)

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 116036-78-3

References:

1. Ueda, H., Yoshihara, Y., Fukushima, N., Shiomi, H., Nakamura, A. and Takagi, H. Kyotorphin (tyrosine-arginine) synthetase in rat brain synaptosomes. J. Biol. Chem. 262 (1987) 8165-8173. [PMID: 3597366]

[EC 6.3.2.24 created 1992]

EC 6.3.2.25

Accepted name: tubulin—tyrosine ligase

Reaction: ATP + detyrosinated α-tubulin + L-tyrosine = α-tubulin + ADP + phosphate

Systematic name: α-tubulin:L-tyrosine ligase (ADP-forming)

Comments: L-Tyrosine is linked via a peptide bond to the C-terminus of de-tyrosinated α-tubulin (des-Tyrω-α-tubulin). The enzyme is highly specific for α-tubulin and moderately specific for ATP and L-tyrosine. L-Phenylalanine and 3,4-dihydroxy-L-phenylalanine are transferred but with higher Km values.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 60321-03-1

References:

1. Wehland, J., Schröder, H.C., Weber, K. Isolation and purification of tubulin-tyrosine ligase. Methods Enzymol. 134 (1986) 170-179. [PMID: 3821560]

2. Rudiger, M., Wehland, J., Weber, K. The carboxy-terminal peptide of detyrosinated alpha tubulin provides a minimal system to study the substrate specificity of tubulin-tyrosine ligase. Eur. J. Biochem. 220 (1994) 309-320. [PMID: 7510228]

[EC 6.3.2.25 created 1999]

EC 6.3.2.26

Accepted name: N-(5-amino-5-carboxypentanoyl)-L-cysteinyl-D-valine synthase

Reaction: 3 ATP + L-2-aminohexanedioate + L-cysteine + L-valine + H2O = 3 AMP + 3 diphosphate + N-[L-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine

For diagram click here and possible mechanism click here.

Other name(s): L-δ-(α-aminoadipoyl)-L-cysteinyl-D-valine synthetase; ACV synthetase; L-α-aminoadipyl-cysteinyl-valine synthetase

Systematic name: L-2-aminohexanedioate:L-cysteine:L-valine ligase (AMP-forming, valine-inverting)

Comments: Requires Mg2+. The enzyme contains 4'-phosphopantetheine, which may be involved in the mechanism of the reaction. Forms part of the penicillin biosynthesis pathway (for pathway, click here).

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number: 57219-73-5

References:

1. Byford, M.F., Baldwin, J.E., Shiau, C.-Y. and Schofield, C.J. The mechanism of ACV synthetase. Chem. Rev. 97 (1997) 2631-2649. [PMID: 11851475]

2. Theilgaard, H.B., Kristiansen, K.N., Henriksen, C.M. and Nielsen, J. Purification and characterization of δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine synthetase from Penicillium chrysogenum. Biochem. J. 327 (1997) 185-191. [PMID: 9355751]

[EC 6.3.2.26 created 2002]

[EC 6.3.2.27 Deleted entry: The activity is covered by two independent enzymes, EC 6.3.2.38 N2-citryl-N6-acetyl-N6-hydroxylysine synthase, and EC 6.3.2.39, aerobactin synthase (EC 6.3.2.27 created 2002, modified 2006, deleted 2012)]

[EC 6.3.2.28 Transferred entry: L-amino-acid α-ligase. Now EC 6.3.2.49, L-alanine-L-anticapsin ligase (EC 6.3.2.28 created 2006, deleted 2015)]

EC 6.3.2.29

Accepted name: cyanophycin synthase (L-aspartate-adding)

Reaction: ATP + [L-Asp(4-L-Arg)]n + L-Asp = ADP + phosphate + [L-Asp(4-L-Arg)]nL-Asp

For diagram click here.

Glossary: cyanophycin = [L-Asp(4-L-Arg)]n = N-β-aspartylarginine = [L-4-(L-arginin-2-N-yl)aspartic acid]n = poly{N4-[(1S)-1-carboxy-4-guanidinobutyl]-L-asparagine}

Other name(s): CphA (ambiguous); CphA1 (ambiguous); CphA2 (ambiguous); cyanophycin synthetase (ambiguous); multi-L-arginyl-poly-L-aspartate synthase (ambiguous)

Systematic name: cyanophycin:L-aspartate ligase (ADP-forming)

Comments: Requires Mg2+ for activity. Both this enzyme and EC 6.3.2.30, cyanophycin synthase (L-arginine-adding), are required for the elongation of cyanophycin, which is a protein-like cell inclusion that is unique to cyanobacteria and acts as a temporary nitrogen store [2]. Both enzymes are found in the same protein but have different active sites [2,4]. Both L-Asp and L-Arg must be present before either enzyme will display significant activity [2].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Aboulmagd, E., Oppermann-Sanio, F.B. and Steinbüchel, A. Molecular characterization of the cyanophycin synthetase from Synechocystis sp. strain PCC6308. Arch. Microbiol. 174 (2000) 297-306. [PMID: 11131019]

2. Aboulmagd, E., Oppermann-Sanio, F.B. and Steinbüchel, A. Purification of Synechocystis sp. strain PCC6308 cyanophycin synthetase and its characterization with respect to substrate and primer specificity. Appl. Environ. Microbiol. 67 (2001) 2176-2182. [PMID: 11319097]

3. Allen, M.M., Hutchison, F. and Weathers, P.J. Cyanophycin granule polypeptide formation and degradation in the cyanobacterium Aphanocapsa 6308. J. Bacteriol. 141 (1980) 687-693. [PMID: 6767688]

4. Berg, H., Ziegler, K., Piotukh, K., Baier, K., Lockau, W. and Volkmer-Engert, R. Biosynthesis of the cyanobacterial reserve polymer multi-L-arginyl-poly-L-aspartic acid (cyanophycin): mechanism of the cyanophycin synthetase reaction studied with synthetic primers. Eur. J. Biochem. 267 (2000) 5561-5570. [PMID: 10951215]

5. Ziegler, K., Deutzmann, R. and Lockau, W. Cyanophycin synthetase-like enzymes of non-cyanobacterial eubacteria: characterization of the polymer produced by a recombinant synthetase of Desulfitobacterium hafniense. Z. Naturforsch. [C] 57 (2002) 522-529. [PMID: 12132696]

6. Ziegler, K., Diener, A., Herpin, C., Richter, R., Deutzmann, R. and Lockau, W. Molecular characterization of cyanophycin synthetase, the enzyme catalyzing the biosynthesis of the cyanobacterial reserve material multi-L-arginyl-poly-L-aspartate (cyanophycin). Eur. J. Biochem. 254 (1998) 154-159. [PMID: 9652408]

[EC 6.3.2.29 created 2007]

EC 6.3.2.30

Accepted name: cyanophycin synthase (L-arginine-adding)

Reaction: ATP + [L-Asp(4-L-Arg)]nL-Asp + L-Arg = ADP + phosphate + [L-Asp(4-L-Arg)]n+1

For diagram click here.

Glossary: cyanophycin = [L-Asp(4-L-Arg)]n = N-β-aspartylarginine = [L-4-(L-arginin-2-N-yl)aspartic acid]n = poly{N4-[(1S)-1-carboxy-4-guanidinobutyl]-L-asparagine}

Other name(s): CphA (ambiguous); CphA1 (ambiguous); CphA2 (ambiguous); cyanophycin synthetase (ambiguous); multi-L-arginyl-poly-L-aspartate synthase (ambiguous)

Systematic name: cyanophycin:L-arginine ligase (ADP-forming)

Comments: Requires Mg2+ for activity. Both this enzyme and EC 6.3.2.29, cyanophycin synthase (L-aspartate-adding), are required for the elongation of cyanophycin, which is a protein-like cell inclusion that is unique to cyanobacteria and acts as a temporary nitrogen store [2]. Both enzymes are found in the same protein but have different active sites [2,4]. Both L-Asp and L-Arg must be present before either enzyme will display significant activity [2]. Canavanine and lysine can be incoporated into the polymer instead of arginine [2].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Aboulmagd, E., Oppermann-Sanio, F.B. and Steinbüchel, A. Molecular characterization of the cyanophycin synthetase from Synechocystis sp. strain PCC6308. Arch. Microbiol. 174 (2000) 297-306. [PMID: 11131019]

2. Aboulmagd, E., Oppermann-Sanio, F.B. and Steinbüchel, A. Purification of Synechocystis sp. strain PCC6308 cyanophycin synthetase and its characterization with respect to substrate and primer specificity. Appl. Environ. Microbiol. 67 (2001) 2176-2182. [PMID: 11319097]

3. Allen, M.M., Hutchison, F. and Weathers, P.J. Cyanophycin granule polypeptide formation and degradation in the cyanobacterium Aphanocapsa 6308. J. Bacteriol. 141 (1980) 687-693. [PMID: 6767688]

4. Berg, H., Ziegler, K., Piotukh, K., Baier, K., Lockau, W. and Volkmer-Engert, R. Biosynthesis of the cyanobacterial reserve polymer multi-L-arginyl-poly-L-aspartic acid (cyanophycin): mechanism of the cyanophycin synthetase reaction studied with synthetic primers. Eur. J. Biochem. 267 (2000) 5561-5570. [PMID: 10951215]

5. Ziegler, K., Deutzmann, R. and Lockau, W. Cyanophycin synthetase-like enzymes of non-cyanobacterial eubacteria: characterization of the polymer produced by a recombinant synthetase of Desulfitobacterium hafniense. Z. Naturforsch. [C] 57 (2002) 522-529. [PMID: 12132696]

6. Ziegler, K., Diener, A., Herpin, C., Richter, R., Deutzmann, R. and Lockau, W. Molecular characterization of cyanophycin synthetase, the enzyme catalyzing the biosynthesis of the cyanobacterial reserve material multi-L-arginyl-poly-L-aspartate (cyanophycin). Eur. J. Biochem. 254 (1998) 154-159. [PMID: 9652408]

[EC 6.3.2.30 created 2007]

EC 6.3.2.31

Accepted name: coenzyme F420-0:L-glutamate ligase

Reaction: GTP + coenzyme F420-0 + L-glutamate = GDP + phosphate + coenzyme F420-1

For diagram of reaction, click here

Glossary: coenzyme F420

Other name(s): CofE-AF; MJ0768; CofE

Systematic name: L-glutamate:coenzyme F420-0 ligase (GDP-forming)

Comments: This protein catalyses the successive addition of two glutamate residues to cofactor F420 by two distinct and independent reactions. In the reaction described here the enzyme attaches a glutamate via its α-amine group to F420-0. In the second reaction (EC 6.3.2.34, coenzyme F420-1—γ-L-glutamate ligase) it catalyses the addition of a second L-glutamate residue to the γ-carboxyl of the first glutamate.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number:

References:

1. Li, H., Graupner, M., Xu, H. and White, R.H. CofE catalyzes the addition of two glutamates to F420-0 in F420 coenzyme biosynthesis in Methanococcus jannaschii. Biochemistry 42 (2003) 9771-9778. [PMID: 12911320]

2. Nocek, B., Evdokimova, E., Proudfoot, M., Kudritska, M., Grochowski, L.L., White, R.H., Savchenko, A., Yakunin, A.F., Edwards, A. and Joachimiak, A. Structure of an amide bond forming F420:γ-glutamyl ligase from Archaeoglobus fulgidus — a member of a new family of non-ribosomal peptide synthases. J. Mol. Biol. 372 (2007) 456-469. [PMID: 17669425]

[EC 6.3.2.31 created 2010]

EC 6.3.2.32

Accepted name: coenzyme γ-F420-2:α-L-glutamate ligase

Reaction: ATP + coenzyme γ-F420-2 + L-glutamate = ADP + phosphate + coenzyme α-F420-3

For diagram of reaction, click here

Other name(s): MJ1001; CofF protein; γ-F420-2:α-L-glutamate ligase

Systematic name: L-glutamate:coenzyme γ-F420-2 (ADP-forming)

Comments: The enzyme caps the γ-glutamyl tail of the hydride carrier coenzyme F420 [1].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Li, H., Xu, H., Graham, D.E. and White, R.H. Glutathione synthetase homologs encode α-L-glutamate ligases for methanogenic coenzyme F420 and tetrahydrosarcinapterin biosyntheses. Proc. Natl. Acad. Sci. USA 100 (2003) 9785-9790. [PMID: 12909715]

[EC 6.3.2.32 created 2010]

EC 6.3.2.33

Accepted name: tetrahydrosarcinapterin synthase

Reaction: ATP + tetrahydromethanopterin + L-glutamate = ADP + phosphate + 5,6,7,8-tetrahydrosarcinapterin

For diagram of reaction click here.

Other name(s): H4MPT:α-L-glutamate ligase; MJ0620; MptN protein

Systematic name: tetrahydromethanopterin:α-L-glutamate ligase (ADP-forming)

Comments: This enzyme catalyses the biosynthesis of 5,6,7,8-tetrahydrosarcinapterin, a modified form of tetrahydromethanopterin found in the Methanosarcinales. It does not require K+, and does not discriminate between ATP and GTP [1].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Li, H., Xu, H., Graham, D.E. and White, R.H. Glutathione synthetase homologs encode α-L-glutamate ligases for methanogenic coenzyme F420 and tetrahydrosarcinapterin biosyntheses. Proc. Natl. Acad. Sci. USA 100 (2003) 9785-9790. [PMID: 12909715]

[EC 6.3.2.33 created 2010]

EC 6.3.2.34

Accepted name: coenzyme F420-1:γ-L-glutamate ligase

Reaction: GTP + coenzyme F420-1 + L-glutamate = GDP + phosphate + coenzyme γ-F420-2

For diagram of reaction, click here

Glossary: coenzyme F420

Other name(s): F420:γ-glutamyl ligase; CofE-AF; MJ0768; CofE

Systematic name: L-glutamate:coenzyme F420-1 ligase (GDP-forming)

Comments: This protein catalyses the successive addition of two glutamate residues to cofactor F420 by two distinct and independent reactions. In the first reaction (EC 6.3.2.31, coenzyme F420-0—L-glutamate ligase) the enzyme attaches a glutamate via its α-amine group to F420-0. In the second reaction, which is described here, the enzyme catalyses the addition of a second L-glutamate residue to the γ-carboxyl of the first glutamate.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, PDB, CAS registry number:

References:

1. Li, H., Graupner, M., Xu, H. and White, R.H. CofE catalyzes the addition of two glutamates to F420-0 in F420 coenzyme biosynthesis in Methanococcus jannaschii. Biochemistry 42 (2003) 9771-9778. [PMID: 12911320]

2. Nocek, B., Evdokimova, E., Proudfoot, M., Kudritska, M., Grochowski, L.L., White, R.H., Savchenko, A., Yakunin, A.F., Edwards, A. and Joachimiak, A. Structure of an amide bond forming F420:γ-glutamyl ligase from Archaeoglobus fulgidus — a member of a new family of non-ribosomal peptide synthases. J. Mol. Biol. 372 (2007) 456-469. [PMID: 17669425]

[EC 6.3.2.34 created 2010]

EC 6.3.2.35

Accepted name: D-alanine—D-serine ligase

Reaction: D-alanine + D-serine + ATP = D-alanyl-D-serine + ADP + phosphate

Other name(s): VanC; VanE; VanG

Systematic name: D-alanine:D-serine ligase (ADP-forming)

Comments: The product of this enzyme, D-alanyl-D-serine, can be incorporated into the peptidoglycan pentapeptide instead of the usual D-alanyl-D-alanine dipeptide, which is formed by EC 6.3.2.4, D-alanine—D-alanine ligase. The resulting peptidoglycan does not bind the glycopeptide antibiotics vancomycin and teicoplanin, conferring resistance on the bacteria.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Dutka-Malen, S., Molinas, C., Arthur, M. and Courvalin, P. Sequence of the vanC gene of Enterococcus gallinarum BM4174 encoding a D-alanine:D-alanine ligase-related protein necessary for vancomycin resistance. Gene 112 (1992) 53-58. [PMID: 1551598]

2. Park, I.S., Lin, C.H. and Walsh, C.T. Bacterial resistance to vancomycin: overproduction, purification, and characterization of VanC2 from Enterococcus casseliflavus as a D-Ala-D-Ser ligase. Proc. Natl. Acad. Sci. USA 94 (1997) 10040-10044. [PMID: 9294159]

3. Fines, M., Perichon, B., Reynolds, P., Sahm, D.F. and Courvalin, P. VanE, a new type of acquired glycopeptide resistance in Enterococcus faecalis BM4405. Antimicrob. Agents Chemother. 43 (1999) 2161-2164. [PMID: 10471558]

4. Depardieu, F., Bonora, M.G., Reynolds, P.E. and Courvalin, P. The vanG glycopeptide resistance operon from Enterococcus faecalis revisited. Mol. Microbiol. 50 (2003) 931-948. [PMID: 14617152]

5. Watanabe, S., Kobayashi, N., Quinones, D., Hayakawa, S., Nagashima, S., Uehara, N. and Watanabe, N. Genetic Diversity of the Low-Level Vancomycin Resistance Gene vanC-2/vanC-3 and Identification of a Novel vanC Subtype (vanC-4) in Enterococcus casseliflavus. Microb. Drug Resist. 15 (2009) 1-9. [PMID: 19216682]

[EC 6.3.2.35 created 2010]

EC 6.3.2.36

Accepted name: 4-phosphopantoate—β-alanine ligase

Reaction: ATP + (R)-4-phosphopantoate + β-alanine = AMP + diphosphate + (R)-4'-phosphopantothenate

Other name(s): phosphopantothenate synthetase; TK1686 protein

Systematic name: (R)-4-phosphopantoate:β-alanine ligase (AMP-forming)

Comments: The conversion of (R)-pantoate to (R)-4'-phosphopantothenate is part of the pathway leading to biosynthesis of 4'-phosphopantetheine, an essential cofactor of coenzyme A and acyl-carrier protein. In bacteria and eukaryotes this conversion is performed by condensation with β-alanine, followed by phosphrylation (EC 6.3.2.1 [pantoate—β-alanine ligase] and EC 2.7.1.33 [pantothenate kinase], respectively). In archaea the order of these two steps is reversed, and phosphorylation precedes condensation with β-alanine. The two archaeal enzymes that catalyse this conversion are EC 2.7.1.169, pantoate kinase, and this enzyme.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Yokooji, Y., Tomita, H., Atomi, H. and Imanaka, T. Pantoate kinase and phosphopantothenate synthetase, two novel enzymes necessary for CoA biosynthesis in the Archaea. J. Biol. Chem. 284 (2009) 28137-28145. [PMID: 19666462]

[EC 6.3.2.36 created 2011]

EC 6.3.2.37

Accepted name: UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—D-lysine ligase

ATP + UDP-N-acetyl-α-D-muramoyl-L-alanyl-D-glutamate + D-lysine = ADP + phosphate + UDP-N-acetyl-α-D-muramoyl-L-alanyl-γ-D-glutamyl-Nε-D-lysine

Glossary: muramic acid = 2-amino-3-O-[(R)-1-carboxyethyl]-2-deoxy-D-glucose

Other name(s): UDP-MurNAc-L-Ala-D-Glu:D-Lys ligase; D-lysine-adding enzyme

Systematic name: UDP-N-acetyl-α-D-muramoyl-L-alanyl-D-glutamate:D-lysine γ-ligase (ADP-forming)

Comments: Involved in the synthesis of cell-wall peptidoglycan. The D-lysine is attached to the peptide chain at the N6 position. The enzyme from Thermotoga maritima also performs the reaction of EC 6.3.2.7, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate—L-lysine ligase.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Boniface, A., Bouhss, A., Mengin-Lecreulx, D. and Blanot, D. The MurE synthetase from Thermotoga maritima is endowed with an unusual D-lysine adding activity. J. Biol. Chem. 281 (2006) 15680-15686. [PMID: 16595662]

[EC 6.3.2.37 created 2011, modified 2015]

EC 6.3.2.38

Accepted name: N2-citryl-N6-acetyl-N6-hydroxylysine synthase

Reaction: 2 ATP + citrate + N6-acetyl-N6-hydroxy-L-lysine + H2O = 2 ADP + 2 phosphate + N2-citryl-N6-acetyl-N6-hydroxy-L-lysine

For diagram of reaction click here.

Other name(s): Nα-citryl-Nε-acetyl-Nε-hydroxylysine synthase; iucA (gene name)

Systematic name: citrate:N6-acetyl-N6-hydroxy-L-lysine ligase (ADP-forming)

Comments: Requires Mg2+. Aerobactin is one of a group of high-affinity iron chelators known as siderophores and is produced under conditions of iron deprivation [5]. It is a dihydroxamate comprising two molecules of N6-acetyl-N6-hydroxy-L-lysine and one molecule of citrate. This enzyme catalyses the first of two synthase reactions to link N6-acetyl-N6-hydroxy-L-lysine and citrate [4,5].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Appanna, D.L., Grundy, B.J., Szczepan, E.W. and Viswanatha, T. Aerobactin synthesis in a cell-free system of Aerobacter aerogenes 62-1. Biochim. Biophys. Acta 801 (1984) 437-443.

2. Gibson, F. and Magrath, D.I. The isolation and characterization of a hydroxamic acid (aerobactin) formed by Aerobacter aerogenes 62-I. Biochim. Biophys. Acta 192 (1969) 175-184. [PMID: 4313071]

3. Maurer, P.J. and Miller, M. Microbial iron chelators: total synthesis of aerobactin and its constituent amino acid, N6-acetyl-N6-hydroxylysine. J. Am. Chem. Soc. 104 (1982) 3096-3101.

4. de Lorenzo, V., Bindereif, A., Paw, B.H. and Neilands, J.B. Aerobactin biosynthesis and transport genes of plasmid ColV-K30 in Escherichia coli K-12. J. Bacteriol. 165 (1986) 570-578. [PMID: 2935523]

5. Challis, G.L. A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases. ChemBioChem 6 (2005) 601-611. [PMID: 15719346]

[EC 6.3.2.38 created 2012]

EC 6.3.2.39

Accepted name: aerobactin synthase

Reaction: 2 ATP + N2-citryl-N6-acetyl-N6-hydroxy-L-lysine + N6-acetyl-N6-hydroxy-L-lysine + H2O = 2 ADP + 2 phosphate + aerobactin

For diagram of reaction click here.

Other name(s): iucC (gene name)

Systematic name: N2-citryl-N6-acetyl-N6-hydroxy-L-lysine:N6-acetyl-N6-hydroxy-L-lysine ligase (ADP-forming)

Comments: Requires Mg2+. Aerobactin is one of a group of high-affinity iron chelators known as siderophores and is produced under conditions of iron deprivation [6]. It is a dihydroxamate comprising two molecules of N6-acetyl-N6-hydroxy-L-lysine and one molecule of citric acid. This enzyme catalyses the second of two synthase reactions to link N6-acetyl-N6-hydroxy-L-lysine and citrate [3,4,5].

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Appanna, D.L., Grundy, B.J., Szczepan, E.W. and Viswanatha, T. Aerobactin synthesis in a cell-free system of Aerobacter aerogenes 62-1. Biochim. Biophys. Acta 801 (1984) 437-443.

2. Gibson, F. and Magrath, D.I. The isolation and characterization of a hydroxamic acid (aerobactin) formed by Aerobacter aerogenes 62-I. Biochim. Biophys. Acta 192 (1969) 175-184. [PMID: 4313071]

3. Maurer, P.J. and Miller, M. Microbial iron chelators: total synthesis of aerobactin and its constituent amino acid, N6-acetyl-N6-hydroxylysine. J. Am. Chem. Soc. 104 (1982) 3096-3101.

4. de Lorenzo, V., Bindereif, A., Paw, B.H. and Neilands, J.B. Aerobactin biosynthesis and transport genes of plasmid ColV-K30 in Escherichia coli K-12. J. Bacteriol. 165 (1986) 570-578. [PMID: 2935523]

5. de Lorenzo, V. and Neilands, J.B. Characterization of iucA and iucC genes of the aerobactin system of plasmid ColV-K30 in Escherichia coli. J. Bacteriol. 167 (1986) 350-355. [PMID: 3087960]

6. Challis, G.L. A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases. ChemBioChem 6 (2005) 601-611. [PMID: 15719346]

[EC 6.3.2.39 created 2012]

EC 6.3.2.40

Accepted name: cyclopeptine synthase

Reaction: 2 ATP + S-adenosyl-L-methionine + anthranilate + L-phenylalanine = cyclopeptine + 2 AMP + 2 diphosphate + S-adenosyl-L-homocysteine

For diagram of reaction click here.

Glossary: cyclopeptine = (3S)-3-benzyl-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione

Systematic name: S-adenosyl-L-methionine:anthranilate:L-phenylalanine ligase (cyclopeptine forming)

Comments: Cyclopeptine synthase is the key enzyme of benzodiazepine alkaloid biosynthesis in the fungus Penicillium cyclopium. The enzyme is a non-ribosomal peptide synthase.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Lerbs, W. and Luckner, M. Cyclopeptine synthetase activity in surface cultures of Penicillium cyclopium. J. Basic Microbiol. 25 (1985) 387-391. [PMID: 2995633]

2. Gerlach, M, Schwelle, N., Lerbs, W. and Luckner, M. Enzymatic synthesis of cyclopeptine intermediates in Penicillium cyclopium. Phytochemistry 24 (1985) 1935-1939.

[EC 6.3.2.40 created 2013]

EC 6.3.2.41

Accepted name: N-acetylaspartylglutamate synthase

Reaction: ATP + N-acetyl-L-aspartate + L-glutamate = ADP + phosphate + N-acetyl-L-aspartyl-L-glutamate

Other name(s): N-acetylaspartylglutamate synthetase; NAAG synthetase; NAAGS; RIMKLA (gene name) (ambiguous); RIMKLB (gene name) (ambiguous)

Systematic name: N-acetyl-L-aspartate:L-glutamate ligase (ADP, N-acetyl-L-aspartyl-L-glutamate-forming)

Comments: The enzyme, found in animals, produces the neurotransmitter N-acetyl-L-aspartyl-L-glutamate. One isoform also has the activity of EC 6.3.1.17, β-citrylglutamate synthase [2], while another isoform has the activity of EC 6.3.2.42, N-acetylaspartylglutamylglutamate synthase [3].

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Becker, I., Lodder, J., Gieselmann, V. and Eckhardt, M. Molecular characterization of N-acetylaspartylglutamate synthetase. J. Biol. Chem. 285 (2010) 29156-29164. [PMID: 20643647]

2. Collard, F., Stroobant, V., Lamosa, P., Kapanda, C.N., Lambert, D.M., Muccioli, G.G., Poupaert, J.H., Opperdoes, F. and Van Schaftingen, E. Molecular identification of N-acetylaspartylglutamate synthase and β-citrylglutamate synthase. J. Biol. Chem. 285 (2010) 29826-29833. [PMID: 20657015]

3. Lodder-Gadaczek, J., Becker, I., Gieselmann, V., Wang-Eckhardt, L. and Eckhardt, M. N-acetylaspartylglutamate synthetase II synthesizes N-acetylaspartylglutamylglutamate. J. Biol. Chem. 286 (2011) 16693-16706. [PMID: 21454531]

[EC 6.3.2.41 created 2014]

EC 6.3.2.42

Accepted name: N-acetylaspartylglutamylglutamate synthase

Reaction: 2 ATP + N-acetyl-L-aspartate + 2 L-glutamate = 2 ADP + 2 phosphate + N-acetyl-L-aspartyl-L-glutamyl-L-glutamate

Other name(s): N-acetylaspartylglutamylglutamate synthetase; NAAG(2) synthase; NAAG synthetase II; NAAGS-II; RIMKLA (gene name) (ambiguous)

Systematic name: N-acetyl-L-aspartate:L-glutamate ligase (ADP, N-acetyl-L-aspartyl-L-glutamyl-L-glutamate-forming)

Comments: The enzyme, found in mammals, also has the activity of EC 6.3.2.41, N-acetylaspartylglutamate synthase.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Lodder-Gadaczek, J., Becker, I., Gieselmann, V., Wang-Eckhardt, L. and Eckhardt, M. N-acetylaspartylglutamate synthetase II synthesizes N-acetylaspartylglutamylglutamate. J. Biol. Chem. 286 (2011) 16693-16706. [PMID: 21454531]

[EC 6.3.2.42 created 2014]

EC 6.3.2.43

Accepted name: [lysine-biosynthesis-protein LysW]—L-2-aminoadipate ligase

Reaction: ATP + [lysine-biosynthesis-protein LysW]-C-terminal-L-glutamate + L-2-aminoadipate = ADP + phosphate + [lysine-biosynthesis-protein LysW]-C-terminal-γ-(L-2-aminoadip-2-yl)-L-glutamate

Other name(s): α-aminoadipate-lysW ligase lysX (gene name); LysX (ambiguous); AAA—LysW ligase

Systematic name: [lysine-biosynthesis-protein LysW]-C-terminal-L-glutamate:L-2-aminoadipate ligase (ADP-forming)

Comments: The enzymes from the thermophilic bacterium Thermus thermophilus and the thermophilic archaea Sulfolobus acidocaldarius and Sulfolobus tokodaii protect the amino group of L-2-aminoadipate by conjugation to the carrier protein LysW. This reaction is part of the lysine biosynthesis pathway in these organisms.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Vassylyeva, M.N., Sakai, H., Matsuura, T., Sekine, S., Nishiyama, M., Terada, T., Shirouzu, M., Kuramitsu, S., Vassylyev, D.G. and Yokoyama, S. Cloning, expression, purification, crystallization and initial crystallographic analysis of the lysine-biosynthesis LysX protein from Thermus thermophilus HB8. Acta Crystallogr. D Biol. Crystallogr. 59 (2003) 1651-1652. [PMID: 12925802]

2. Horie, A., Tomita, T., Saiki, A., Kono, H., Taka, H., Mineki, R., Fujimura, T., Nishiyama, C., Kuzuyama, T. and Nishiyama, M. Discovery of proteinaceous N-modification in lysine biosynthesis of Thermus thermophilus. Nat. Chem. Biol. 5 (2009) 673-679. [PMID: 19620981]

3. Ouchi, T., Tomita, T., Horie, A., Yoshida, A., Takahashi, K., Nishida, H., Lassak, K., Taka, H., Mineki, R., Fujimura, T., Kosono, S., Nishiyama, C., Masui, R., Kuramitsu, S., Albers, S.V., Kuzuyama, T. and Nishiyama, M. Lysine and arginine biosyntheses mediated by a common carrier protein in Sulfolobus. Nat. Chem. Biol. 9 (2013) 277-283. [PMID: 23434852]

[EC 6.3.2.43 created 2014]

EC 6.3.2.44

Accepted name: pantoate—β-alanine ligase (ADP-forming)

Reaction: ATP + (R)-pantoate + β-alanine = ADP + phosphate + (R)-pantothenate

For diagram of reaction click here.

Glossary: (R)-pantoate = (2R)-2,4-dihydroxy-3,3-dimethylbutanoate
(R)-pantothenate = 3-[(2R)-2,4-dihydroxy-3,3-dimethylbutanamido]propanoate

Other name(s): pantothenate synthetase (ambiguous); pantoate—β-alanine ligase (ambiguous)

Systematic name: (R)-pantoate:β-alanine ligase (ADP-forming)

Comments: The enzyme, characterized from the archaeon Methanosarcina mazei, is involved in the biosynthesis of pantothenate. It is different from EC 6.3.2.1, the AMP-forming pantoate-β-alanine ligase found in bacteria and eukaryota.

Links to other databases: BRENDA, EXPASY, KEGG, Metacyc, CAS registry number:

References:

1. Ronconi, S., Jonczyk, R. and Genschel, U. A novel isoform of pantothenate synthetase in the Archaea. FEBS J. 275 (2008) 2754-2764. [PMID: 18422645]

[EC 6.3.2.44 created 2014]

EC 6.3.2.45

Accepted name: UDP-N-acetylmuramate L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate ligase

Reaction: ATP + UDP-N-acetyl-α-D-muramate + L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate = ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate

Glossary: meso-2,6-diaminoheptanedioate = meso-2,6-diaminopimelate

Other name(s): murein peptide ligase; Mpl; yjfG (gene name); UDP-MurNAc:L-Ala-γ-D-Glu-meso-A2pm ligase; UDP-N-acetylmuramate:L-alanyl-γ-D-glutamyl-meso-diaminopimelate ligase

Systematic name: UDP-N-acetylmuramate:L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioate ligase

Comments: The enzyme catalyses the reincorporation into peptidoglycan of the tripeptide L-alanyl-γ-D-glutamyl-2,6-meso-diaminoheptanedioate released during the maturation and constant remodeling of this bacterial cell wall polymer that occur during cell growth and division. The enzyme can also use the tetrapeptide L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioyl-D-alanine or the pentapeptide L-alanyl-γ-D-glutamyl-meso-2,6-diaminoheptanedioyl-D-alanyl-D-alanine in vivo and in vitro. Requires Mg2+.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Mengin-Lecreulx, D., van Heijenoort, J. and Park, J.T. Identification of the mpl gene encoding UDP-N-acetylmuramate: L-alanyl-γ-D-glutamyl-meso-diaminopimelate ligase in Escherichia coli and its role in recycling of cell wall peptidoglycan. J. Bacteriol. 178 (1996) 5347-5352. [PMID: 8808921]

2. Herve, M., Boniface, A., Gobec, S., Blanot, D. and Mengin-Lecreulx, D. Biochemical characterization and physiological properties of Escherichia coli UDP-N-acetylmuramate:L-alanyl-γ-D-glutamyl-meso-diaminopimelate ligase. J. Bacteriol. 189 (2007) 3987-3995. [PMID: 17384195]

[EC 6.3.2.45 created 2014]

EC 6.3.2.46

Accepted name: fumarate—(S)-2,3-diaminopropanoate ligase

Reaction: ATP + fumarate + (S)-2,3-diaminopropanoate = AMP + diphosphate + N3-fumaroyl-(S)-2,3-diaminopropanoate

Glossary: N3-fumaroyl-(S)-2,3-diaminopropanoate = (2E)-4-{[(2S)-2-amino-2-carboxyethyl]amino}-4-oxobut-2-enoate

Other name(s): DdaG

Systematic name: fumarate:(S)-2,3-diaminopropanoate ligase (AMP-forming)

Comments: The enzyme, characterized from the bacterium Enterobacter agglomerans, is involved in biosynthesis of dapdiamide tripeptide antibiotics, a family of fumaramoyl- and epoxysuccinamoyl-peptides named for the presence of an (S)-2,3-diaminopropanoate (DAP) moiety and two amide linkages in their scaffold.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Hollenhorst, M.A., Clardy, J. and Walsh, C.T. The ATP-dependent amide ligases DdaG and DdaF assemble the fumaramoyl-dipeptide scaffold of the dapdiamide antibiotics. Biochemistry 48 (2009) 10467-10472. [PMID: 19807062]

[EC 6.3.2.46 created 2015]

EC 6.3.2.47

Accepted name: dapdiamide synthase

Reaction: (1) ATP + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanine + L-valine = ADP + phosphate + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-valine
(2) ATP + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanine + L-isoleucine = ADP + phosphate + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-isoleucine
(3) ATP + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanine + L-leucine = ADP + phosphate + 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-leucine
(4) ATP + 3-({[(2R,3R)-3-carbamoyloxiran-2-yl]carbonyl}amino)-L-alanine + L-valine = ADP + phosphate + 3-({[(2R,3R)-3-carbamoyloxiran-2-yl]carbonyl}amino)-L-alanyl-L-valine

Glossary: dapdiamide A = 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-valine
dapdiamide B = 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-isoleucine
dapdiamide C = 3-{[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanyl-L-leucine

Other name(s): DdaF; dapdiamide A synthase

Systematic name: {[(2E)-4-amino-4-oxobut-2-enoyl]amino}-L-alanine:L-valine ligase (ADP-forming)

Comments: The enzyme, characterized from the bacterium Pantoea agglomerans, is involved in biosynthesis of dapdiamide tripeptide antibiotics, a family of fumaramoyl- and epoxysuccinamoyl-peptides named for the presence of an (S)-2,3-diaminopropanoate (DAP) moiety and two amide linkages in their scaffold.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Hollenhorst, M.A., Clardy, J. and Walsh, C.T. The ATP-dependent amide ligases DdaG and DdaF assemble the fumaramoyl-dipeptide scaffold of the dapdiamide antibiotics. Biochemistry 48 (2009) 10467-10472. [PMID: 19807062]

2. Hollenhorst, M.A., Bumpus, S.B., Matthews, M.L., Bollinger, J.M., Jr., Kelleher, N.L. and Walsh, C.T. The nonribosomal peptide synthetase enzyme DdaD tethers N(β)-fumaramoyl-L-2,3-diaminopropionate for Fe(II)/α-ketoglutarate-dependent epoxidation by DdaC during dapdiamide antibiotic biosynthesis. J. Am. Chem. Soc. 132 (2010) 15773-15781. [PMID: 20945916]

[EC 6.3.2.47 created 2015, modified 2016]

EC 6.3.2.48

Accepted name: L-arginine-specific L-amino acid ligase

Reaction: ATP + L-arginine + an L-amino acid = ADP + phosphate + an L-arginyl-L-amino acid

Other name(s): RizA; L-amino acid ligase RizA

Systematic name: L-arginine:L-amino acid ligase (ADP-forming)

Comments: The enzyme, characterized from the bacterium Bacillus subtilis, requires Mn2+ for activity. It shows strict substrate specificity toward L-arginine as the first (N-terminal) amino acid of the product. The second amino acid could be any standard protein-building amino acid except for L-proline.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Kino, K., Kotanaka, Y., Arai, T. and Yagasaki, M. A novel L-amino acid ligase from Bacillus subtilis NBRC3134, a microorganism producing peptide-antibiotic rhizocticin. Biosci. Biotechnol. Biochem. 73 (2009) 901-907. [PMID: 19352016]

[EC 6.3.2.48 created 2015]

EC 6.3.2.49

Accepted name: L-alanine-L-anticapsin ligase

Reaction: ATP + L-alanine + L-anticapsin = ADP + phosphate + bacilysin

For diagram of reaction click here.

Glossary: L-anticapsin = 3-[(1R,2S,6R)-5-oxo-7-oxabicyclo[4.1.0]hept-2-yl]-L-alanine
bacilysin = L-alanyl-3-[(1R,2S,6R)-5-oxo-7-oxabicyclo[4.1.0]hept-2-yl]-L-alanine

Other name(s): BacD; alanine-anticapsin ligase; L-Ala-L-anticapsin ligase; ywfE (gene name)

Systematic name: L-alanine:L-anticapsin ligase (ADP-forming)

Comments: The enzyme, characterized from the bacterium Bacillus subtilis, is involved in the biosynthesis of the nonribosomally synthesized dipeptide antibiotic bacilysin, composed of L-alanine and L-anticapsin. The enzyme requires Mg2+ or Mn2+ for activity, and has a broad substrate specificity in vitro [1].

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Tabata, K., Ikeda, H. and Hashimoto, S. ywfE in Bacillus subtilis codes for a novel enzyme, L-amino acid ligase. J. Bacteriol. 187 (2005) 5195-5202. [PMID: 16030213]

2. Tsuda, T., Suzuki, T. and Kojima, S. Crystallization and preliminary X-ray diffraction analysis of Bacillus subtilis YwfE, an L-amino-acid ligase. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 68 (2012) 203-206. [PMID: 22298000]

3. Shomura, Y., Hinokuchi, E., Ikeda, H., Senoo, A., Takahashi, Y., Saito, J., Komori, H., Shibata, N., Yonetani, Y. and Higuchi, Y. Structural and enzymatic characterization of BacD, an L-amino acid dipeptide ligase from Bacillus subtilis. Protein Sci. 21 (2012) 707-716. [PMID: 22407814]

4. Parker, J.B. and Walsh, C.T. Action and timing of BacC and BacD in the late stages of biosynthesis of the dipeptide antibiotic bacilysin. Biochemistry 52 (2013) 889-901. [PMID: 23317005]

[EC 6.3.2.49 created 2006 as EC 6.3.2.28, trasferred 2015 to EC 6.3.2.49]

EC 6.3.2.50

Accepted name: tenuazonic acid synthetase

Reaction: ATP + L-isoleucine + acetoacetyl-CoA = AMP + diphosphate + tenuazonic acid + CoA

Glossary: tenuazonic acid = (5S)-3-acetyl-5-[(2S)-butan-2-yl]-4-hydroxy-1,5-dihydro-2H-pyrrol-2-one

Other name(s): TAS1 (gene name)

Systematic name: L-isoleucine:acetoacetyl-CoA ligase (tenuazonic acid-forming)

Comments: This fungal enzyme, isolated from Magnaporthe oryzae, is an non-ribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) hybrid protein that consists of condensation (C), adenylation (A) and peptidyl-carrier protein (PCP) domains in the NRPS portion and a ketosynthase (KS) domain in the PKS portion. ATP is required for activation of isoleucine, which is then condensed with acetoacetyl-CoA. Cyclization and release from the enzyme are catalysed by the KS domain.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Yun, C.S., Motoyama, T. and Osada, H. Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme. Nat Commun 6 (2015) 8758. [PMID: 26503170]

[EC 6.3.2.50 created 2017]

EC 6.3.2.51

Accepted name: phosphopantothenate—cysteine ligase (ATP)

Reaction: ATP + (R)-4'-phosphopantothenate + L-cysteine = AMP + diphosphate + N-[(R)-4'-phosphopantothenoyl]-L-cysteine

For diagram of reaction click here.

Other name(s): phosphopantothenoylcysteine synthetase (ambiguous); PPCS (gene name)

Systematic name: (R)-4'-phosphopantothenate:L-cysteine ligase (ATP-utilizing)

Comments: A key enzyme in the production of coenzyme A. The eukaryotic enzyme requires ATP, in contrast to the bacterial enzyme, EC 6.3.2.5, phosphopantothenate—cysteine ligase, which requires CTP.

Links to other databases: BRENDA, EXPASY, KEGG, MetaCyc, CAS registry number:

References:

1. Daugherty, M. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J. Biol. Chem. 277 (2002) 21431-21439. [PMID: 11923312]

2. Manoj, N., Strauss, E., Begley, T.P. and Ealick, S.E. Structure of human phosphopantothenoylcysteine synthetase at 2.3 Å Resolution. Structure 11 (2003) 927-936. [PMID: 12906824]

3. Kupke, T., Hernandez-Acosta, P. and Culianez-Macia, F.A. 4'-phosphopantetheine and coenzyme A biosynthesis in plants. J. Biol. Chem. 278 (2003) 38229-38237. [PMID: 12860978]

[EC 6.3.2.51 created 2017]


Continued with EC 6.3.3 to EC 6.3.5
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