DDL_MYCTU
ID DDL_MYCTU Reviewed; 373 AA.
AC P9WP31; L0TBF6; P95114;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=D-alanine--D-alanine ligase {ECO:0000255|HAMAP-Rule:MF_00047};
DE EC=6.3.2.4 {ECO:0000255|HAMAP-Rule:MF_00047, ECO:0000269|PubMed:20956591, ECO:0000269|PubMed:23286234};
DE AltName: Full=D-Ala-D-Ala ligase {ECO:0000255|HAMAP-Rule:MF_00047};
DE AltName: Full=D-alanine:D-alanine ligase {ECO:0000303|PubMed:20956591, ECO:0000303|PubMed:23286234};
DE AltName: Full=D-alanylalanine synthetase {ECO:0000255|HAMAP-Rule:MF_00047};
GN Name=ddl {ECO:0000255|HAMAP-Rule:MF_00047, ECO:0000303|PubMed:20956591,
GN ECO:0000303|PubMed:23286234}; Synonyms=ddlA; OrderedLocusNames=Rv2981c;
GN ORFNames=MTCY349.06;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, KINETIC MECHANISM, AND PATHWAY.
RX PubMed=23286234; DOI=10.1111/febs.12108;
RA Prosser G.A., de Carvalho L.P.;
RT "Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-
RT alanine:D-alanine ligase by the antibiotic D-cycloserine.";
RL FEBS J. 280:1150-1166(2013).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, SUBUNIT, AND PATHWAY.
RC STRAIN=H37Rv;
RX PubMed=20956591; DOI=10.1128/aac.00558-10;
RA Bruning J.B., Murillo A.C., Chacon O., Barletta R.G., Sacchettini J.C.;
RT "Structure of the Mycobacterium tuberculosis D-alanine:D-alanine ligase, a
RT target of the antituberculosis drug D-cycloserine.";
RL Antimicrob. Agents Chemother. 55:291-301(2011).
CC -!- FUNCTION: Catalyzes the ATP-driven ligation of two D-alanine molecules
CC to form the D-alanyl-D-alanine dipeptide. This molecule is a key
CC building block in peptidoglycan biosynthesis. {ECO:0000255|HAMAP-
CC Rule:MF_00047, ECO:0000269|PubMed:20956591,
CC ECO:0000269|PubMed:23286234}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + 2 D-alanine = ADP + D-alanyl-D-alanine + H(+) +
CC phosphate; Xref=Rhea:RHEA:11224, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57416,
CC ChEBI:CHEBI:57822, ChEBI:CHEBI:456216; EC=6.3.2.4;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_00047,
CC ECO:0000269|PubMed:20956591, ECO:0000269|PubMed:23286234};
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 -!- ACTIVITY REGULATION: Is inhibited by the antituberculous drug D-
CC cycloserine (DCS), which is a structural analog of D-alanine
CC (PubMed:20956591, PubMed:23286234). Is activated by K(+)
CC (PubMed:23286234). {ECO:0000269|PubMed:20956591,
CC ECO:0000269|PubMed:23286234}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.075 mM for D-Ala (first D-Ala binding site) (at pH 7.3)
CC {ECO:0000269|PubMed:23286234};
CC KM=3.6 mM for D-Ala (second D-Ala binding site) (at pH 7.3)
CC {ECO:0000269|PubMed:23286234};
CC KM=0.31 mM for ATP (at pH 7.3) {ECO:0000269|PubMed:23286234};
CC Note=kcat is 9.7 sec(-1) (at pH 7.3). {ECO:0000269|PubMed:23286234};
CC -!- PATHWAY: Cell wall biogenesis; peptidoglycan biosynthesis.
CC {ECO:0000255|HAMAP-Rule:MF_00047, ECO:0000305|PubMed:20956591,
CC ECO:0000305|PubMed:23286234}.
CC -!- SUBUNIT: Homodimer. {ECO:0000305|PubMed:20956591}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_00047}.
CC -!- MISCELLANEOUS: Follows an ordered ter-ter mechanism. ATP is the first
CC substrate to bind and is necessary for subsequent binding of D-alanine
CC or DCS. ADP is the final product to dissociate.
CC {ECO:0000269|PubMed:23286234}.
CC -!- SIMILARITY: Belongs to the D-alanine--D-alanine ligase family.
CC {ECO:0000255|HAMAP-Rule:MF_00047}.
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DR EMBL; AL123456; CCP45786.1; -; Genomic_DNA.
DR PIR; B70673; B70673.
DR RefSeq; NP_217497.1; NC_000962.3.
DR RefSeq; WP_003912011.1; NZ_NVQJ01000099.1.
DR PDB; 3LWB; X-ray; 2.10 A; A/B=1-373.
DR PDBsum; 3LWB; -.
DR AlphaFoldDB; P9WP31; -.
DR SMR; P9WP31; -.
DR STRING; 83332.Rv2981c; -.
DR ChEMBL; CHEMBL2030; -.
DR DrugCentral; P9WP31; -.
DR PaxDb; P9WP31; -.
DR DNASU; 888415; -.
DR GeneID; 888415; -.
DR KEGG; mtu:Rv2981c; -.
DR TubercuList; Rv2981c; -.
DR eggNOG; COG1181; Bacteria.
DR OMA; NTTPGMT; -.
DR PhylomeDB; P9WP31; -.
DR BioCyc; MetaCyc:G185E-7236-MON; -.
DR BRENDA; 6.3.2.4; 3445.
DR UniPathway; UPA00219; -.
DR PRO; PR:P9WP31; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008716; F:D-alanine-D-alanine ligase activity; IDA:MTBBASE.
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; IDA:MTBBASE.
DR GO; GO:0008360; P:regulation of cell shape; 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; ATP-binding; Cell shape; Cell wall biogenesis/degradation;
KW Cytoplasm; Ligase; Magnesium; Manganese; Metal-binding; Nucleotide-binding;
KW Peptidoglycan synthesis; Reference proteome.
FT CHAIN 1..373
FT /note="D-alanine--D-alanine ligase"
FT /id="PRO_0000177844"
FT DOMAIN 156..363
FT /note="ATP-grasp"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT BINDING 184..239
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT BINDING 318
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT BINDING 330
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT BINDING 330
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT BINDING 332
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00047"
FT STRAND 11..18
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 26..37
FT /evidence="ECO:0007829|PDB:3LWB"
FT TURN 40..42
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 43..50
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 56..59
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 103..108
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 111..115
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 126..134
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 138..141
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 143..150
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 152..161
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 169..172
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 181..187
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 191..197
FT /evidence="ECO:0007829|PDB:3LWB"
FT TURN 200..203
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 205..207
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 210..212
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 213..221
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 225..231
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 234..244
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 250..252
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 256..259
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 266..271
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 273..277
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 283..287
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 292..308
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 313..322
FT /evidence="ECO:0007829|PDB:3LWB"
FT STRAND 325..334
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 342..349
FT /evidence="ECO:0007829|PDB:3LWB"
FT HELIX 354..367
FT /evidence="ECO:0007829|PDB:3LWB"
SQ SEQUENCE 373 AA; 39710 MW; FD7838E8B7526B53 CRC64;
MSANDRRDRR VRVAVVFGGR SNEHAISCVS AGSILRNLDS RRFDVIAVGI TPAGSWVLTD
ANPDALTITN RELPQVKSGS GTELALPADP RRGGQLVSLP PGAGEVLESV DVVFPVLHGP
YGEDGTIQGL LELAGVPYVG AGVLASAVGM DKEFTKKLLA ADGLPVGAYA VLRPPRSTLH
RQECERLGLP VFVKPARGGS SIGVSRVSSW DQLPAAVARA RRHDPKVIVE AAISGRELEC
GVLEMPDGTL EASTLGEIRV AGVRGREDSF YDFATKYLDD AAELDVPAKV DDQVAEAIRQ
LAIRAFAAID CRGLARVDFF LTDDGPVINE INTMPGFTTI SMYPRMWAAS GVDYPTLLAT
MIETTLARGV GLH
