VANA_ENTFC
ID VANA_ENTFC Reviewed; 343 AA.
AC P25051;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Vancomycin/teicoplanin A-type resistance protein VanA;
DE EC=6.1.2.1;
DE AltName: Full=D-alanine--D-lactate ligase;
DE AltName: Full=VanA ligase;
GN Name=vanA;
OS Enterococcus faecium (Streptococcus faecium).
OG Plasmid pIP816.
OC Bacteria; Firmicutes; Bacilli; Lactobacillales; Enterococcaceae;
OC Enterococcus.
OX NCBI_TaxID=1352;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PROTEIN SEQUENCE OF 1-9.
RC STRAIN=BM4147;
RX PubMed=2266943; DOI=10.1007/bf00262430;
RA Dutka-Malen S., Molinas C., Arthur M., Courvalin P.;
RT "The VANA glycopeptide resistance protein is related to D-alanyl-D-alanine
RT ligase cell wall biosynthesis enzymes.";
RL Mol. Gen. Genet. 224:364-372(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=BM4147;
RX PubMed=8380148; DOI=10.1128/jb.175.1.117-127.1993;
RA Arthur M., Molinas C., Depardieu F., Courvalin P.;
RT "Characterization of Tn1546, a Tn3-related transposon conferring
RT glycopeptide resistance by synthesis of depsipeptide peptidoglycan
RT precursors in Enterococcus faecium BM4147.";
RL J. Bacteriol. 175:117-127(1993).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RC STRAIN=BM4147;
RX PubMed=1931965; DOI=10.1021/bi00107a007;
RA Bugg T.D.H., Wright G.D., Dutka-Malen S., Arthur M., Courvalin P.,
RA Walsh C.T.;
RT "Molecular basis for vancomycin resistance in Enterococcus faecium BM4147:
RT biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin
RT resistance proteins VanH and VanA.";
RL Biochemistry 30:10408-10415(1991).
RN [4]
RP CHARACTERIZATION OF REACTION PRODUCT.
RX PubMed=1522072; DOI=10.1128/jb.174.18.5982-5984.1992;
RA Handwerger S., Pucci M.J., Volk K.J., Liu J., Lee M.S.;
RT "The cytoplasmic peptidoglycan precursor of vancomycin-resistant
RT Enterococcus faecalis terminates in lactate.";
RL J. Bacteriol. 174:5982-5984(1992).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH MAGNESIUM; ADP AND
RP INHIBITOR.
RX PubMed=10908650; DOI=10.1073/pnas.150116497;
RA Roper D.I., Huyton T., Vagin A., Dodson G.;
RT "The molecular basis of vancomycin resistance in clinically relevant
RT Enterococci: crystal structure of D-alanyl-D-lactate ligase (VanA).";
RL Proc. Natl. Acad. Sci. U.S.A. 97:8921-8925(2000).
CC -!- FUNCTION: Required for high-level resistance to glycopeptide
CC antibiotics. D-Ala--D-Ala ligase of altered specificity which catalyzes
CC ester bond formation between D-Ala and various D-hydroxy acids;
CC produces a peptidoglycan which does not terminate in D-alanine but in
CC D-lactate, thus preventing vancomycin or teicoplanin binding.
CC {ECO:0000269|PubMed:1931965}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-lactate + ATP + D-alanine = ADP + D-alanyl-(R)-lactate +
CC phosphate; Xref=Rhea:RHEA:37347, ChEBI:CHEBI:16004,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57416,
CC ChEBI:CHEBI:61166, ChEBI:CHEBI:456216; EC=6.1.2.1;
CC Evidence={ECO:0000269|PubMed:1931965};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250};
CC Note=Binds 2 magnesium or manganese ions per subunit. {ECO:0000250};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=7.1 mM for D-lactate {ECO:0000269|PubMed:1931965};
CC KM=3.8 mM for D-alanine {ECO:0000269|PubMed:1931965};
CC KM=0.6 mM for 2-hydroxybutyrate {ECO:0000269|PubMed:1931965};
CC KM=3.2 mM for 2-hydroxyvalerate {ECO:0000269|PubMed:1931965};
CC KM=11 mM for 2-hydroxycaproate {ECO:0000269|PubMed:1931965};
CC -!- SUBCELLULAR LOCATION: Cell membrane; Peripheral membrane protein;
CC Cytoplasmic side.
CC -!- INDUCTION: By vancomycin, mediated by VanS/VanR.
CC -!- SIMILARITY: Belongs to the D-alanine--D-alanine ligase family.
CC {ECO:0000305}.
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DR EMBL; X56895; CAA40215.1; -; Genomic_DNA.
DR EMBL; M97297; AAA65956.1; -; Genomic_DNA.
DR PIR; S12254; CESOVM.
DR RefSeq; WP_001079845.1; NZ_WQKY01000109.1.
DR RefSeq; YP_001019035.1; NC_008821.1.
DR RefSeq; YP_001974796.1; NC_010980.1.
DR RefSeq; YP_002128399.1; NC_011140.1.
DR RefSeq; YP_976077.1; NC_008768.1.
DR PDB; 1E4E; X-ray; 2.50 A; A/B=1-343.
DR PDBsum; 1E4E; -.
DR AlphaFoldDB; P25051; -.
DR SMR; P25051; -.
DR BindingDB; P25051; -.
DR ChEMBL; CHEMBL6037; -.
DR KEGG; ag:CAA40215; -.
DR BioCyc; MetaCyc:MON-15466; -.
DR BRENDA; 6.1.2.1; 2096.
DR SABIO-RK; P25051; -.
DR EvolutionaryTrace; P25051; -.
DR PRO; PR:P25051; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-UniRule.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008716; F:D-alanine-D-alanine ligase activity; IDA:CACAO.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0071555; P:cell wall organization; IEA:UniProtKB-KW.
DR GO; GO:0009252; P:peptidoglycan biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0008360; P:regulation of cell shape; IEA:UniProtKB-KW.
DR GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
DR Gene3D; 3.30.1490.20; -; 1.
DR HAMAP; MF_00047; Dala_Dala_lig; 1.
DR InterPro; IPR011761; ATP-grasp.
DR InterPro; IPR013815; ATP_grasp_subdomain_1.
DR InterPro; IPR000291; D-Ala_lig_Van_CS.
DR InterPro; IPR005905; D_ala_D_ala.
DR InterPro; IPR011095; Dala_Dala_lig_C.
DR InterPro; IPR011127; Dala_Dala_lig_N.
DR InterPro; IPR016185; PreATP-grasp_dom_sf.
DR Pfam; PF07478; Dala_Dala_lig_C; 1.
DR Pfam; PF01820; Dala_Dala_lig_N; 1.
DR PIRSF; PIRSF039102; Ddl/VanB; 1.
DR SUPFAM; SSF52440; SSF52440; 1.
DR TIGRFAMs; TIGR01205; D_ala_D_alaTIGR; 1.
DR PROSITE; PS50975; ATP_GRASP; 1.
DR PROSITE; PS00843; DALA_DALA_LIGASE_1; 1.
DR PROSITE; PS00844; DALA_DALA_LIGASE_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic resistance; ATP-binding; Cell membrane;
KW Cell shape; Cell wall biogenesis/degradation; Direct protein sequencing;
KW Ligase; Magnesium; Manganese; Membrane; Metal-binding; Nucleotide-binding;
KW Peptidoglycan synthesis; Plasmid.
FT CHAIN 1..343
FT /note="Vancomycin/teicoplanin A-type resistance protein
FT VanA"
FT /id="PRO_0000177917"
FT DOMAIN 137..338
FT /note="ATP-grasp"
FT BINDING 133
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 169..171
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 177..178
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 207..214
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 241
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 244
FT /ligand="substrate"
FT BINDING 304..305
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 305
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:10908650"
FT BINDING 305
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:10908650"
FT BINDING 307
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:10908650"
FT STRAND 4..11
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 17..30
FT /evidence="ECO:0007829|PDB:1E4E"
FT TURN 33..35
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 36..43
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 49..53
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 65..69
FT /evidence="ECO:0007829|PDB:1E4E"
FT TURN 73..75
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 77..82
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 85..90
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 92..96
FT /evidence="ECO:0007829|PDB:1E4E"
FT TURN 101..103
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 104..106
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 107..115
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 119..121
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 124..131
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 133..142
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 150..153
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 161..163
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 168..174
FT /evidence="ECO:0007829|PDB:1E4E"
FT TURN 177..180
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 182..184
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 187..189
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 190..197
FT /evidence="ECO:0007829|PDB:1E4E"
FT TURN 198..200
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 202..208
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 212..222
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 232..239
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 243..245
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 246..248
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 249..251
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 254..258
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 266..282
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 286..295
FT /evidence="ECO:0007829|PDB:1E4E"
FT STRAND 301..309
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 317..324
FT /evidence="ECO:0007829|PDB:1E4E"
FT HELIX 329..341
FT /evidence="ECO:0007829|PDB:1E4E"
SQ SEQUENCE 343 AA; 37443 MW; AAA48E3B2AD48E03 CRC64;
MNRIKVAILF GGCSEEHDVS VKSAIEIAAN INKEKYEPLY IGITKSGVWK MCEKPCAEWE
NDNCYSAVLS PDKKMHGLLV KKNHEYEINH VDVAFSALHG KSGEDGSIQG LFELSGIPFV
GCDIQSSAIC MDKSLTYIVA KNAGIATPAF WVINKDDRPV AATFTYPVFV KPARSGSSFG
VKKVNSADEL DYAIESARQY DSKILIEQAV SGCEVGCAVL GNSAALVVGE VDQIRLQYGI
FRIHQEVEPE KGSENAVITV PADLSAEERG RIQETAKKIY KALGCRGLAR VDMFLQDNGR
IVLNEVNTLP GFTSYSRYPR MMAAAGIALP ELIDRLIVLA LKG
