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Database: UniProt
Entry: P25051
LinkDB: P25051
Original site: P25051 
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   05-DEC-2018, entry version 134.
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-
RT   alanine 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
RP   BIOPHYSICOCHEMICAL 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
RT   BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by
RT   vancomycin 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
RP   AND 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
CC       catalyzes ester bond formation between D-Ala and various D-hydroxy
CC       acids; produces a peptidoglycan which does not terminate in D-
CC       alanine but in D-lactate, thus preventing vancomycin or
CC       teicoplanin binding. {ECO:0000269|PubMed:1931965}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(R)-lactate + ATP + D-alanine = ADP + D-alanyl-(R)-
CC         lactate + 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.
CC       {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}.
DR   EMBL; X56895; CAA40215.1; -; Genomic_DNA.
DR   EMBL; M97297; AAA65956.1; -; Genomic_DNA.
DR   PIR; S12254; CESOVM.
DR   RefSeq; WP_001079845.1; NZ_UFYT01000005.1.
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   ProteinModelPortal; P25051; -.
DR   SMR; P25051; -.
DR   BindingDB; P25051; -.
DR   ChEMBL; CHEMBL6037; -.
DR   PRIDE; P25051; -.
DR   GeneID; 4670249; -.
DR   GeneID; 4783144; -.
DR   GeneID; 6385877; -.
DR   GeneID; 6779647; -.
DR   KEGG; ag:CAA40215; -.
DR   KO; K15739; -.
DR   BioCyc; MetaCyc:MONOMER-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;
KW   Direct protein sequencing; Ligase; Magnesium; Manganese; Membrane;
KW   Metal-binding; Nucleotide-binding; Peptidoglycan synthesis; Plasmid.
FT   CHAIN         1    343       Vancomycin/teicoplanin A-type resistance
FT                                protein VanA.
FT                                /FTId=PRO_0000177917.
FT   DOMAIN      137    338       ATP-grasp.
FT   NP_BIND     169    171       ATP.
FT   NP_BIND     177    178       ATP.
FT   NP_BIND     207    214       ATP.
FT   NP_BIND     304    305       ATP.
FT   METAL       305    305       Magnesium 1.
FT                                {ECO:0000269|PubMed:10908650}.
FT   METAL       305    305       Magnesium 2.
FT                                {ECO:0000269|PubMed:10908650}.
FT   METAL       307    307       Magnesium 2.
FT                                {ECO:0000269|PubMed:10908650}.
FT   BINDING     133    133       ATP.
FT   BINDING     241    241       ATP; via amide nitrogen.
FT   BINDING     244    244       Substrate.
FT   STRAND        4     11       {ECO:0000244|PDB:1E4E}.
FT   HELIX        17     30       {ECO:0000244|PDB:1E4E}.
FT   TURN         33     35       {ECO:0000244|PDB:1E4E}.
FT   STRAND       36     43       {ECO:0000244|PDB:1E4E}.
FT   STRAND       49     53       {ECO:0000244|PDB:1E4E}.
FT   STRAND       65     69       {ECO:0000244|PDB:1E4E}.
FT   TURN         73     75       {ECO:0000244|PDB:1E4E}.
FT   STRAND       77     82       {ECO:0000244|PDB:1E4E}.
FT   STRAND       85     90       {ECO:0000244|PDB:1E4E}.
FT   STRAND       92     96       {ECO:0000244|PDB:1E4E}.
FT   TURN        101    103       {ECO:0000244|PDB:1E4E}.
FT   STRAND      104    106       {ECO:0000244|PDB:1E4E}.
FT   HELIX       107    115       {ECO:0000244|PDB:1E4E}.
FT   STRAND      119    121       {ECO:0000244|PDB:1E4E}.
FT   HELIX       124    131       {ECO:0000244|PDB:1E4E}.
FT   HELIX       133    142       {ECO:0000244|PDB:1E4E}.
FT   STRAND      150    153       {ECO:0000244|PDB:1E4E}.
FT   HELIX       161    163       {ECO:0000244|PDB:1E4E}.
FT   STRAND      168    174       {ECO:0000244|PDB:1E4E}.
FT   TURN        177    180       {ECO:0000244|PDB:1E4E}.
FT   STRAND      182    184       {ECO:0000244|PDB:1E4E}.
FT   HELIX       187    189       {ECO:0000244|PDB:1E4E}.
FT   HELIX       190    197       {ECO:0000244|PDB:1E4E}.
FT   TURN        198    200       {ECO:0000244|PDB:1E4E}.
FT   STRAND      202    208       {ECO:0000244|PDB:1E4E}.
FT   STRAND      212    222       {ECO:0000244|PDB:1E4E}.
FT   STRAND      232    239       {ECO:0000244|PDB:1E4E}.
FT   HELIX       243    245       {ECO:0000244|PDB:1E4E}.
FT   STRAND      246    248       {ECO:0000244|PDB:1E4E}.
FT   HELIX       249    251       {ECO:0000244|PDB:1E4E}.
FT   STRAND      254    258       {ECO:0000244|PDB:1E4E}.
FT   HELIX       266    282       {ECO:0000244|PDB:1E4E}.
FT   STRAND      286    295       {ECO:0000244|PDB:1E4E}.
FT   STRAND      301    309       {ECO:0000244|PDB:1E4E}.
FT   HELIX       317    324       {ECO:0000244|PDB:1E4E}.
FT   HELIX       329    341       {ECO:0000244|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
//
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