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physiological function
the enzyme is a key enzyme in the emergence of high level resistance to vancomycin in Enterococcus
physiological function
-
Enterococcus faecium 10/96A from Brazil is resistant to vancomycin with a minimum inhibitory concentration MIC of 0.256 mg/ml. Cytoplasmic peptidoglycan precursors from cells of strain 10/96A grown in the presence or absence of 0.004 mg of vancomycin/ml contain in both cases 95% UDP-MurNAc-pentadepsipeptide, 3% UDPMurNAc-pentapeptide, and 2% UDP-MurNAc-tetrapeptide, supporting the role of VanD4 as a D-Ala-D-Lac ligase and indicating that glycopeptide resistance is expressed constitutively
physiological function
-
in the presence of vancomycin, production of the VanB D-Ala:D-Lac ligase is induced, which overcomes the defect in the synthesis of peptidoglycan precursors ending in D-AlaD-Ala due to a lack of functional Ddl D-Ala-D-Ala ligase. Vancomycin-dependent strain BM4660 synthesizes mainly UDP-MurNAc-pentadepsipeptide, 44%, whereas large amounts of UDP-MurNActripeptide, 39%, and small amounts of pentapeptide, 12%, and tetrapeptide, 5%, are present. The presence of tripeptide in large quantity suggests that the VanB ligase may not be sufficiently active to synthesize D-AlaD-Lac as rapidly as tripeptide is produced
physiological function
-
resistance to glycopeptides in Enterococcus faecium BM4416 is due to synthesis of late peptidoglycan precursors ending in D-AlaD-Lac. Strain BM4416 mainly produces UDP-MurNAc-pentadepsipeptide, 69%, terminating in D-AlaD-Lac, UDP-MurNAc-tetrapeptide, 24%, and UDP-MurNAc-tripeptide, 7%. No significant amounts of UDP-MurNAc-pentapeptide are found. Constitutive resistance is encoded by a vanD operon closely related to that of Enterococcus faecium BM4339 and also located in the chromosome. Both VanD-type strains produce an inactivated D-Ala:D-Ala ligase due to an insertion in the ddl gene
physiological function
-
the vanD gene encodes a D-Ala:D-Lac ligase related to VanA and VanB which is not transferable by conjugation. It renders the cells constitutively resistant to vancomycin with a minimum inhibitory concentration MIC of 0.064 mg/ml and to low levels of teicoplanin, MIC 0.004 mg/ml. Cytoplasmic peptidoglycan precursors that accumulate are mainly UDP-MurNAc-pentadepsipeptide, UDP-MurNAc-tetrapeptide, and UDP-MurNAc-tripeptide. The large proportion of UDP-MurNAc-pentadepsipeptide indicates that the mechanism of vancomycin resistance in BM4339 is similar to that in VanA and VanB strains. The presence of UDP-MurNAc-tripeptide implies that the rate of synthesis of D-AlaD-Ala or D-AlaD-Lac substrates is limiting
physiological function
-
VanA is a D-alanine:D-alanine ligase of altered substrate specificity. VanA catalyzes ester bond formation between D-alanine and the D-hydroxy acid products of VanH, the best substrate being D-2-hydroxybutyrate. The VanA product D-alanyl-D-2-hydroxybutyrate can then be incorporated into the UDPMurNAc-pentapeptide peptidoglycan precursor
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Perichon, B.; Casadewall, B.; Reynolds, P.; Courvalin, P.
Glycopeptide-resistant Enterococcus faecium BM4416 is a VanD-type strain with an impaired D-alanine:D-alanine ligase
Antimicrob. Agents Chemother.
44
1346-1348
2000
Enterococcus faecium, Enterococcus faecium BM4416
brenda
Sova, M.; Cadez, G.; Turk, S.; Majce, V.; Polanc, S.; Batson, S.; Lloyd, A.J.; Roper, D.I.; Fishwick, C.W.; Gobec, S.
Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB)
Bioorg. Med. Chem. Lett.
19
1376-1379
2009
Enterococcus faecium
brenda
Huyton, T.; Roper, D.I.
Crystallization and preliminary X-ray characterization of VanA from Enterococcus faecium BM4147: towards the molecular basis of bacterial resistance to the glycopeptide antibiotic vancomycin
Acta Crystallogr. Sect. D
55
1481-1483
1999
Enterococcus faecium
brenda
Perichon, B.; Reynolds, P.; Courvalin, P.
VanD-type glycopeptide-resistant Enterococcus faecium BM4339
Antimicrob. Agents Chemother.
41
2016-2018
1997
Enterococcus faecium, Enterococcus faecium BM4339
brenda
Dalla Costa, L.M.; Reynolds, P.E.; Souza, H.A.; Souza, D.C.; Palepou, M.F.; Woodford, N.
Characterization of a divergent vanD-type resistance element from the first glycopeptide-resistant strain of Enterococcus faecium isolated in Brazil
Antimicrob. Agents Chemother.
44
3444-3446
2000
Enterococcus faecium, Enterococcus faecium 10/96A
brenda
San Millan, A.; Depardieu, F.; Godreuil, S.; Courvalin, P.
VanB-type Enterococcus faecium clinical isolate successively inducibly resistant to, dependent on, and constitutively resistant to vancomycin
Antimicrob. Agents Chemother.
53
1974-1982
2009
Enterococcus faecium, Enterococcus faecium BM 4660
brenda
Bugg, T.D.; Wright, G.D.; Dutka-Malen, S.; Arthur, M.; Courvalin, P.; Walsh, C.T.
Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA
Biochemistry
30
10408-10415
1991
Enterococcus faecium, Enterococcus faecium BM4147
brenda
Healy, V.L.; Mullins, L.S.; Li, X.; Hall, S.E.; Raushel, F.M.; Walsh, C.T.
D-AlaD-X ligases: evaluation of D-alanyl phosphate intermediate by MIX, PIX and rapid quench studies
Chem. Biol.
7
505-514
2000
Enterococcus faecium
brenda
Bouvier, G.; Duclert-Savatier, N.; Desdouits, N.; Meziane-Cherif, D.; Blondel, A.; Courvalin, P.; Nilges, M.; Malliavin, T.E.
Functional motions modulating VanA ligand binding unraveled by self-organizing maps
J. Chem. Inf. Model.
54
289-301
2014
Enterococcus faecium (P25051), Enterococcus faecium, Enterococcus faecium BM4147 (P25051)
brenda
Nakipoglu, M.; Yilmaz, F.; Icgen, B.
vanA Gene harboring enterococcal and non-enterococcal isolates expressing high level vancomycin and teicoplanin resistance reservoired in surface waters
Bull. Environ. Contam. Toxicol.
98
712-719
2017
Comamonas testosteroni, Comamonas testosteroni Ni11, Enterococcus faecalis, Enterococcus faecalis Cr07, Enterococcus faecalis E07, Enterococcus faecalis Pb06, Enterococcus faecium, Enterococcus faecium 330, Pseudomonas fluorescens, Pseudomonas fluorescens SDS3, Pseudomonas koreensis, Pseudomonas koreensis Cu12, Pseudomonas koreensis Hg10, Pseudomonas koreensis Hg11, Pseudomonas plecoglossicida, Pseudomonas plecoglossicida Ag10, Raoultella planticola, Raoultella planticola Ag11
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