DAPA_MYCTU
ID DAPA_MYCTU Reviewed; 300 AA.
AC P9WP25; L0TDG5; O33295; P63945;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 41.
DE RecName: Full=4-hydroxy-tetrahydrodipicolinate synthase {ECO:0000255|HAMAP-Rule:MF_00418};
DE Short=HTPA synthase {ECO:0000255|HAMAP-Rule:MF_00418};
DE EC=4.3.3.7 {ECO:0000255|HAMAP-Rule:MF_00418};
GN Name=dapA {ECO:0000255|HAMAP-Rule:MF_00418}; OrderedLocusNames=Rv2753c;
GN ORFNames=MTV002.18c;
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 AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [3]
RP CRYSTALLIZATION, AND SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17077492; DOI=10.1107/s1744309106039844;
RA Kefala G., Weiss M.S.;
RT "Cloning, expression, purification, crystallization and preliminary X-ray
RT diffraction analysis of DapA (Rv2753c) from Mycobacterium tuberculosis.";
RL Acta Crystallogr. F 62:1116-1119(2006).
RN [4]
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 [5]
RP X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) OF 2-300, FUNCTION, KINETIC
RP PARAMETERS, ACTIVITY REGULATION, AND SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=18062777; DOI=10.1042/bj20071360;
RA Kefala G., Evans G.L., Griffin M.D., Devenish S.R., Pearce F.G.,
RA Perugini M.A., Gerrard J.A., Weiss M.S., Dobson R.C.;
RT "Crystal structure and kinetic study of dihydrodipicolinate synthase from
RT Mycobacterium tuberculosis.";
RL Biochem. J. 411:351-360(2008).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 2-300 OF MUTANT ARG-204 IN
RP COMPLEX WITH PYRUVATE, ACTIVE SITE, AND MUTAGENESIS OF ALA-204.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21672512; DOI=10.1016/j.abb.2011.05.014;
RA Evans G., Schuldt L., Griffin M.D., Devenish S.R., Grant Pearce F.,
RA Perugini M.A., Dobson R.C., Jameson G.B., Weiss M.S., Gerrard J.A.;
RT "A tetrameric structure is not essential for activity in
RT dihydrodipicolinate synthase (DHDPS) from Mycobacterium tuberculosis.";
RL Arch. Biochem. Biophys. 512:154-159(2011).
CC -!- FUNCTION: Catalyzes the condensation of (S)-aspartate-beta-semialdehyde
CC [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).
CC {ECO:0000305|PubMed:18062777}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate 4-semialdehyde + pyruvate = (2S,4S)-4-hydroxy-
CC 2,3,4,5-tetrahydrodipicolinate + H(+) + H2O; Xref=Rhea:RHEA:34171,
CC ChEBI:CHEBI:15361, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:67139, ChEBI:CHEBI:537519; EC=4.3.3.7;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_00418};
CC -!- ACTIVITY REGULATION: Is insensitive to feedback inhibition by (S)-
CC lysine. {ECO:0000269|PubMed:18062777}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.17 mM for pyruvate {ECO:0000269|PubMed:18062777};
CC KM=0.43 mM for L-aspartate-4-semialdehyde
CC {ECO:0000269|PubMed:18062777};
CC Vmax=4.42 umol/sec/mg enzyme {ECO:0000269|PubMed:18062777};
CC Note=kcat is 138 sec(-1).;
CC -!- PATHWAY: Amino-acid biosynthesis; L-lysine biosynthesis via DAP
CC pathway; (S)-tetrahydrodipicolinate from L-aspartate: step 3/4.
CC {ECO:0000255|HAMAP-Rule:MF_00418}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:17077492,
CC ECO:0000269|PubMed:18062777, ECO:0000269|PubMed:21672512}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_00418}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC -!- SIMILARITY: Belongs to the DapA family. {ECO:0000255|HAMAP-
CC Rule:MF_00418}.
CC -!- CAUTION: Was originally thought to be a dihydrodipicolinate synthase
CC (DHDPS), catalyzing the condensation of (S)-aspartate-beta-semialdehyde
CC [(S)-ASA] and pyruvate to dihydrodipicolinate (DHDP). However, it was
CC shown in E.coli that the product of the enzymatic reaction is not
CC dihydrodipicolinate but in fact (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-
CC dipicolinic acid (HTPA), and that the consecutive dehydration reaction
CC leading to DHDP is not spontaneous but catalyzed by DapB.
CC {ECO:0000305}.
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DR EMBL; AL123456; CCP45552.1; -; Genomic_DNA.
DR PIR; H70879; H70879.
DR RefSeq; NP_217269.1; NC_000962.3.
DR RefSeq; WP_003900564.1; NZ_NVQJ01000020.1.
DR PDB; 1XXX; X-ray; 2.28 A; A/B/C/D/E/F/G/H=2-300.
DR PDB; 3L21; X-ray; 2.10 A; A/B/C/D/E/F=2-300.
DR PDB; 5J5D; X-ray; 2.40 A; A=1-300.
DR PDBsum; 1XXX; -.
DR PDBsum; 3L21; -.
DR PDBsum; 5J5D; -.
DR AlphaFoldDB; P9WP25; -.
DR SMR; P9WP25; -.
DR STRING; 83332.Rv2753c; -.
DR ChEMBL; CHEMBL6063; -.
DR PaxDb; P9WP25; -.
DR DNASU; 888289; -.
DR GeneID; 45426740; -.
DR GeneID; 888289; -.
DR KEGG; mtu:Rv2753c; -.
DR TubercuList; Rv2753c; -.
DR eggNOG; COG0329; Bacteria.
DR OMA; GMDACVP; -.
DR PhylomeDB; P9WP25; -.
DR BRENDA; 4.3.3.7; 3445.
DR UniPathway; UPA00034; UER00017.
DR PRO; PR:P9WP25; -.
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:0008840; F:4-hydroxy-tetrahydrodipicolinate synthase activity; IDA:MTBBASE.
DR GO; GO:0019877; P:diaminopimelate biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0009089; P:lysine biosynthetic process via diaminopimelate; IDA:MTBBASE.
DR CDD; cd00950; DHDPS; 1.
DR Gene3D; 3.20.20.70; -; 1.
DR HAMAP; MF_00418; DapA; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR005263; DapA.
DR InterPro; IPR002220; DapA-like.
DR InterPro; IPR020625; Schiff_base-form_aldolases_AS.
DR InterPro; IPR020624; Schiff_base-form_aldolases_CS.
DR PANTHER; PTHR12128; PTHR12128; 1.
DR Pfam; PF00701; DHDPS; 1.
DR PIRSF; PIRSF001365; DHDPS; 1.
DR PRINTS; PR00146; DHPICSNTHASE.
DR SMART; SM01130; DHDPS; 1.
DR TIGRFAMs; TIGR00674; dapA; 1.
DR PROSITE; PS00665; DHDPS_1; 1.
DR PROSITE; PS00666; DHDPS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amino-acid biosynthesis; Cytoplasm;
KW Diaminopimelate biosynthesis; Lyase; Lysine biosynthesis;
KW Reference proteome; Schiff base.
FT CHAIN 1..300
FT /note="4-hydroxy-tetrahydrodipicolinate synthase"
FT /id="PRO_0000103128"
FT ACT_SITE 143
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418"
FT ACT_SITE 171
FT /note="Schiff-base intermediate with substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418,
FT ECO:0000269|PubMed:21672512"
FT BINDING 55
FT /ligand="pyruvate"
FT /ligand_id="ChEBI:CHEBI:15361"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418"
FT BINDING 211
FT /ligand="pyruvate"
FT /ligand_id="ChEBI:CHEBI:15361"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418"
FT SITE 54
FT /note="Part of a proton relay during catalysis"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418"
FT SITE 117
FT /note="Part of a proton relay during catalysis"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_00418"
FT MUTAGEN 204
FT /note="A->R: Exists as dimer in solution. Has similar
FT activity to the wild-type enzyme. Slight decrease in
FT affinity for substrates."
FT /evidence="ECO:0000269|PubMed:21672512"
FT HELIX 8..12
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 14..18
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 31..43
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 47..53
FT /evidence="ECO:0007829|PDB:3L21"
FT TURN 54..57
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 58..60
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 63..77
FT /evidence="ECO:0007829|PDB:3L21"
FT TURN 78..80
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 81..86
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 92..105
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 108..113
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 122..133
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 140..144
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 146..149
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 155..162
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 167..172
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 177..187
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 190..195
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 196..198
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 199..205
FT /evidence="ECO:0007829|PDB:3L21"
FT STRAND 209..213
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 215..231
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 234..243
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 245..266
FT /evidence="ECO:0007829|PDB:3L21"
FT HELIX 283..295
FT /evidence="ECO:0007829|PDB:3L21"
SQ SEQUENCE 300 AA; 30858 MW; 71CB322661416367 CRC64;
MTTVGFDVAA RLGTLLTAMV TPFSGDGSLD TATAARLANH LVDQGCDGLV VSGTTGESPT
TTDGEKIELL RAVLEAVGDR ARVIAGAGTY DTAHSIRLAK ACAAEGAHGL LVVTPYYSKP
PQRGLQAHFT AVADATELPM LLYDIPGRSA VPIEPDTIRA LASHPNIVGV KDAKADLHSG
AQIMADTGLA YYSGDDALNL PWLAMGATGF ISVIAHLAAG QLRELLSAFG SGDIATARKI
NIAVAPLCNA MSRLGGVTLS KAGLRLQGID VGDPRLPQVA ATPEQIDALA ADMRAASVLR
