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Information on EC 6.3.2.13 - UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-2,6-diaminopimelate ligase and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WJL3
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6.3.2.13 UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-2,6-diaminopimelate ligaseIUBMB 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.
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The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Reaction Schemes
Synonyms
mur ligase, amide ligase, meso-diaminopimelate-adding enzyme, udp-n-acetylmuramyl tripeptide synthetase, udp-n-acetylmuramoyl-l-alanyl-d-glutamate-2,6-diaminopimelate ligase, mure synthetase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Diaminopimelic-adding enzyme
-
-
-
-
mDAP ligase
-
-
-
-
Meso-diaminopimelate-adding enzyme
-
-
-
-
MurE synthetase
-
-
-
-
Synthetase, uridine diphospho-N-acetylmuramoylalanyl-D-glutamyl-meso-2,6-diaminopimelate
-
-
-
-
UDP-MurNAc-tripeptide synthetase
-
-
-
-
UDP-N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-2,6-diaminopimelate synthetase
-
-
-
-
UDP-N-acetylmuramyl-tripeptide synthetase
-
-
-
-
UDPMurNAc-L-alanyl-D-glutamate:mDAP ligase (ADP-forming)
-
-
-
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Uridine diphosphate N-acetylmuramyl-L-alanyl-D-glutamate:meso-2,6-diaminopimelate ligase
-
-
-
-
Uridine-diphosphate-N-acetylmuramyl-L-alanyl-D-glutamate:meso-2,6-diaminopimelate synthetase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
carboxylic acid amide formation
-
-
-
-
carboxamide formation
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-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -
SYSTEMATIC NAME
IUBMB Comments
UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:(L)-meso-2,6-diaminoheptanedioate gamma-ligase (ADP-forming)
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.
CAS REGISTRY NUMBER
COMMENTARY
9075-09-6
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + UDP-N-acetylmuramoyl-L-Ala-D-Glu + meso-diaminopimelic acid
ADP + phosphate + UDP-N-acetylmuramoyl-L-Ala-D-Glu-meso-diaminopimelic acid
-
-
-
?
ATP + UDP-N-acetylmuramoyl-L-alanyl-D-glutamate + meso-2,6-diaminoheptanedioate
ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminoheptanedioate
-
-
-
?
ATP + MurNAc-L-Ala-D-Glu + meso-2,6-diaminoheptanedioate
?
-
relative activity wild-type: 14%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + D-Ala-D-Ala
?
-
relative activity wild-type: 5%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + D-Glu
?
-
relative activity wild-type: 13%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + D-Lys
?
-
relative activity wild-type: 9%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + D-ornithine
?
-
relative activity wild-type: 8%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + DL-lanthionine
?
-
relative activity wild-type: 82%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + L-Ala
?
-
relative activity wild-type: 12%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + L-cystathionine
?
-
relative activity wild-type: 12%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + L-Lys
?
-
relative activity wild-type: 7%
-
-
?
ATP + UDP-MurNAc-L-Ala-D-Glu + meso-2,6-diaminoheptanedioate
ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminoheptanedioate
-
relative activity wild-type: 100%
-
-
?
GTP + UDP-MurNAc-L-Ala-D-Glu + meso-2,6-diaminoheptanedioate
GDP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminoheptanedioate
-
relative activity wild-type: 30%
-
-
?
UDP-N-acetylmuramoyl-L-alanyl-D-glutamate + ATP + meso-diaminopimelic acid
ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-diaminopimelic acid
-
-
-
-
?
UTP + UDP-MurNAc-L-Ala-D-Glu + meso-2,6-diaminoheptanedioate
UDP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminoheptanedioate
-
relative activity wild-type: 17%
-
-
?
additional information
?
-
highly specific in adding meso-diaminopimelic acid to UDP-MurNAc-dipeptide. No substrate: L-Lys, D-Lys, m-Lys, L-Ala, D-Ala, L-Glu, D-Glu, Gly, Gly-Gly, DL-ornithine, N-acetylmuramic acid, UDP-N-acetylmuramoyl pentapeptide. ATP-hydrolysis is an absolute requirement for activity
-
-
?
additional information
?
-
MurE is only active in the presence of its specific natural substrates UDP-N-acetylmuramoyl-L-alanine-D-glutamate, meso-2,6-diaminoheptanedioate, and ATP
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + UDP-N-acetylmuramoyl-L-alanyl-D-glutamate + meso-2,6-diaminoheptanedioate
ADP + phosphate + UDP-N-acetylmuramoyl-L-alanyl-D-gamma-glutamyl-meso-2,6-diaminoheptanedioate
-
-
-
?
additional information
?
-
MurE is only active in the presence of its specific natural substrates UDP-N-acetylmuramoyl-L-alanine-D-glutamate, meso-2,6-diaminoheptanedioate, and ATP
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-methyl-2-[(4Z)-tetradec-4-en-1-yl]quinolin-4(1H)-one
-
inhibitory to enzyme and growth inhibitor of Mycobacterium tuberculosis and rapid-growing mycobacteria
1-methyl-2-[(5Z)-tetradec-5-en-1-yl]quinolin-4(1H)-one
-
inhibitory to enzyme and growth inhibitor of Mycobacterium tuberculosis and rapid-growing mycobacteria
2-[(1E)-dec-1-en-1-yl]-1-methylquinolin-4(1H)-one
-
inhibitory to enzyme and growth inhibitor of Mycobacterium tuberculosis and rapid-growing mycobacteria
2-[(1E)-dodec-1-en-1-yl]-1-methylquinolin-4(1H)-one
-
inhibitory to enzyme and growth inhibitor of Mycobacterium tuberculosis and rapid-growing mycobacteria
2-[(1E)-tridec-1-en-1-yl]-1-methylquinolin-4(1H)-one
-
inhibitory to enzyme and growth inhibitor of Mycobacterium tuberculosis and rapid-growing mycobacteria
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.065
meso-2,6-diaminoheptanedioate
-
DELTA1-24 (N-terminal deletion mutant), pH 8.5, 37°C
0.005
UDP-MurNAc-L-Ala-D-Glu
-
mutant K157A, pH 8.5, 37°C, value below
0.019
UDP-MurNAc-L-Ala-D-Glu
-
DELTA1-24 (N-terminal deletion mutant), pH 8.5, 37°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.05
ATP
-
mutant N449D, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
0.06
ATP
-
mutant R451A, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
0.08
ATP
-
mutant K157A, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
0.1
ATP
-
mutant D392A, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
0.56
ATP
-
mutant E220A, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
1.11
ATP
-
N-terminal deletion mutant, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
1.3
ATP
-
wild-type, pH 8.5, 37°C, co-substrate: UDP-MurNAc-L-Ala-D-Glu, meso-2,6-diaminoheptanedioate
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.052
1-methyl-2-[(4Z)-tetradec-4-en-1-yl]quinolin-4(1H)-one
Mycobacterium tuberculosis
-
phosphate-based method, pH 8.5, 37°C
0.159
1-methyl-2-[(4Z)-tetradec-4-en-1-yl]quinolin-4(1H)-one
Mycobacterium tuberculosis
-
HPLC method, pH 8.5, 37°C
0.036
1-methyl-2-[(5Z)-tetradec-5-en-1-yl]quinolin-4(1H)-one
Mycobacterium tuberculosis
-
phosphate-based method, pH 8.5, 37°C
0.095
1-methyl-2-[(5Z)-tetradec-5-en-1-yl]quinolin-4(1H)-one
Mycobacterium tuberculosis
-
HPLC method, pH 8.5, 37°C
0.07
2-[(1E)-dec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
phosphate-based method, pH 8.5, 37°C
0.207
2-[(1E)-dec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
HPLC method, pH 8.5, 37°C
0.072
2-[(1E)-dodec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
phosphate-based method, pH 8.5, 37°C
0.187
2-[(1E)-dodec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
HPLC method, pH 8.5, 37°C
0.052
2-[(1E)-tridec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
phosphate-based method, pH 8.5, 37°C
0.14
2-[(1E)-tridec-1-en-1-yl]-1-methylquinolin-4(1H)-one
Mycobacterium tuberculosis
-
HPLC method, pH 8.5, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
ATP-dependent Mur ligases play essential roles in the biosynthesis of cell wall peptidoglycan as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis
additional information
protein-protein interaction network of MurC, D, E, and F synthetases, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 3.0 A resolution in the presence of the substrate UDP-MurNAc-L-Ala-D-Glu. Protein consists of 3 domains consisting of residues 25-139,140-378 and 379-535, respectively. The UAG ligand binds to both domains 1 and 2 with the UDP portion binding to domain 1 and the peptide to domain 2. The substrate molecule UAG is bound between domains 1 and 2
computational docking of inhibitors to crystal structure. Uracil recognition site is a probable binding site for quinolone inhibitors
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D392A
-
kcat lower than wild-type, Km (meso-2,6-diaminoheptanedioate) and Km (ATP) higher than wild-type, Km (UDP-MurNAc-L-Ala-D-Glu) lower than wild-type, mutant shows hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate is enhanced by at least partial occupation of the uridine nucleotide dipeptide binding site, mutant shows very high activity with all the amino acids, uridine sugar precursors and nucleotides tested compared to wild type and moreover, reaching up to 100%
DELTA1-24
-
N-terminal deletion mutant, kcat comparable to wild-type, Km values comparable to wild-type, mutant shows similar results to the wild-type with all the nucleotides, UDP-MurNAc peptides and amino acids
E220A
-
kcat lower than wild-type, Km (ATP) and Km (UDP-MurNAc-L-Ala-D-Glu), Km (meso-2,6-diaminoheptanedioate) lower than wild-type, mutant shows hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate is enhanced by atleast partial occupation of the uridine nucleotide dipeptide binding site, mutant shows very high activity with all the amino acids, uridine sugar precursors and nucleotides tested compared to wild type and moreover, reaching up to 100%
K157A
-
kcat lower than wild-type, Km (meso-2,6-diaminoheptanedioate), Km (UDP-MurNAc-L-Ala-D-Glu) and Km (ATP) lower than wild-type, mutant shows hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate is enhanced by at least partial occupation of the uridine nucleotide dipeptide binding site, mutant shows very high activity with all the amino acids, uridine sugar precursors and nucleotides tested compared to wild type and moreover, reaching up to 100%
N449D
-
kcat lower than wild-type, Km (ATP) and Km (meso-2,6-diaminoheptanedioate) higher than wild-type, Km (UDP-MurNAc-L-Ala-D-Glu) lower than wild-type, mutant shows similar results to the wild-type with all the nucleotides, UDP-MurNAc peptides and amino acids, except D-Lys, which shows a slightly higher activity for mutant N449D
R451A
-
kcat lower than wild-type, Km (ATP) comparable to wild-type, Km (meso-2,6-diaminoheptanedioate) higher than wild-type, Km (UDP-MurNAc-L-Ala-D-Glu) lower than wild-type, significant activity in the presence of L-Lys, D-Lys, DL-ornithine and D-Glu for mutant R451A with similar activities as wild type for all the nucleotides and UDP-MurNAc peptides tested
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10 - 40
purified recombinant His-tagged enzyme, stable up to
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene murE or Rv2158c, located in the division/cell wall (dcw) cluster,, identification of a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW, recombinant expression of His6-tagged enzyme in Escherichia coli BL21(DE3)/pLysS and Pseudomonas putida KT2442, subcloning in Escherichia coli strain DH5alpha.. Coexpression of genes murC/D/E/F/nat and genes pknA, pknB, murI, dapF, ddlA, namH, Rv2160c, ftsW, ftsQ, ftsZ, sepF, wag31 in Mycobacterium smegmatis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Guzman, J.D.; Wube, A.; Evangelopoulos, D.; Gupta, A.; Huefner, A.; Basavannacharya, C.; Rahman, M.M.; Thomaschitz, C.; Bauer, R.; McHugh, T.D.; Nobeli, I.; Prieto, J.M.; Gibbons, S.; Bucar, F.; Bhakta, S.
Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics
J. Antimicrob. Chemother.
66
1766-1772
2011
Mycobacterium tuberculosis
Basavannacharya, C.; Moody, P.R.; Munshi, T.; Cronin, N.; Keep, N.H.; Bhakta, S.
Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis
Protein Cell
1
1011-1022
2010
Mycobacterium tuberculosis
Basavannacharya, C.; Robertson, G.; Munshi, T.; Keep, N.; Bhakta, S.
ATP-dependent MurE ligase in Mycobacterium tuberculosis: Biochemical and structural characterisation
Tuberculosis
90
16-24
2010
Mycobacterium tuberculosis (P9WJL3), Mycobacterium tuberculosis H37Rv (P9WJL3)
Munshi, T.; Gupta, A.; Evangelopoulos, D.; Guzman, J.D.; Gibbons, S.; Keep, N.H.; Bhakta, S.
Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis
PLoS ONE
8
e60143
2013
Mycobacterium tuberculosis (P9WJL3), Mycobacterium tuberculosis H37Rv (P9WJL3)
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