DHPS1_MYCTU
ID DHPS1_MYCTU Reviewed; 280 AA.
AC P9WND1; L0TG01; O06274; P0A578;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 45.
DE RecName: Full=Dihydropteroate synthase {ECO:0000303|PubMed:10542185};
DE Short=DHPS {ECO:0000303|PubMed:10542185};
DE EC=2.5.1.15 {ECO:0000269|PubMed:10542185, ECO:0000269|PubMed:23118010, ECO:0000269|PubMed:23779105};
DE AltName: Full=Dihydropteroate pyrophosphorylase;
GN Name=folP1; OrderedLocusNames=Rv3608c; ORFNames=MTCY07H7B.14;
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 [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND SUBUNIT.
RC STRAIN=H37Rv;
RX PubMed=10542185; DOI=10.1128/jb.181.21.6814-6821.1999;
RA Nopponpunth V., Sirawaraporn W., Greene P.J., Santi D.V.;
RT "Cloning and expression of Mycobacterium tuberculosis and Mycobacterium
RT leprae dihydropteroate synthase in Escherichia coli.";
RL J. Bacteriol. 181:6814-6821(1999).
RN [2]
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 [3]
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 [4]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RC STRAIN=H37Rv;
RX PubMed=23779105; DOI=10.1074/jbc.m113.475798;
RA Zheng J., Rubin E.J., Bifani P., Mathys V., Lim V., Au M., Jang J., Nam J.,
RA Dick T., Walker J.R., Pethe K., Camacho L.R.;
RT "para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in
RT Mycobacterium tuberculosis.";
RL J. Biol. Chem. 288:23447-23456(2013).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC STRAIN=H37Rv;
RX PubMed=23118010; DOI=10.1126/science.1228980;
RA Chakraborty S., Gruber T., Barry C.E. III, Boshoff H.I., Rhee K.Y.;
RT "Para-aminosalicylic acid acts as an alternative substrate of folate
RT metabolism in Mycobacterium tuberculosis.";
RL Science 339:88-91(2013).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH MAGNESIUM IONS AND
RP PTERIN MONOPHOSPHATE, AND COFACTOR.
RX PubMed=11007651; DOI=10.1006/jmbi.2000.4094;
RA Baca A.M., Sirawaraporn R., Turley S., Sirawaraporn W., Hol W.G.J.;
RT "Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate
RT synthase in complex with pterin monophosphate: new insight into the
RT enzymatic mechanism and sulfa-drug action.";
RL J. Mol. Biol. 302:1193-1212(2000).
RN [7]
RP ERRATUM OF PUBMED:11007651.
RA Baca A.M., Sirawaraporn R., Turley S., Sirawaraporn W., Hol W.G.J.;
RL J. Mol. Biol. 303:843-843(2000).
CC -!- FUNCTION: Catalyzes the condensation of para-aminobenzoate (pABA) with
CC 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-
CC dihydropteroate (H2Pte), the immediate precursor of folate derivatives.
CC {ECO:0000269|PubMed:10542185, ECO:0000269|PubMed:23118010,
CC ECO:0000269|PubMed:23779105}.
CC -!- FUNCTION: Is involved in the bioactivation of the antituberculous drug
CC para-aminosalicylic acid (PAS). PAS is a close structural analog of
CC pABA and acts as an alternative substrate for DHPS, leading to hydroxy-
CC dihydropteroate (H2PtePAS). Metabolomic studies show that PAS, despite
CC its in vitro activity as a competitive inhibitor of DHPS, does not
CC inhibit growth of M.tuberculosis by inhibiting DHPS. PAS exerts its
CC antimycobacterial activity through its effects on M.tuberculosis folate
CC metabolism downstream of DHPS. PAS poisons folate-dependent pathways
CC not only by serving as a replacement substrate for DHPS but also by the
CC products of that reaction serving as replacement substrates and/or
CC inhibitors of subsequent enzymes. {ECO:0000269|PubMed:23118010,
CC ECO:0000269|PubMed:23779105}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate =
CC 7,8-dihydropteroate + diphosphate; Xref=Rhea:RHEA:19949,
CC ChEBI:CHEBI:17836, ChEBI:CHEBI:17839, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:72950; EC=2.5.1.15;
CC Evidence={ECO:0000269|PubMed:10542185, ECO:0000269|PubMed:23118010,
CC ECO:0000269|PubMed:23779105};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminosalicylate
CC = 2-hydroxy-7,8-dihydropteroate + diphosphate; Xref=Rhea:RHEA:53732,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:72950, ChEBI:CHEBI:137598,
CC ChEBI:CHEBI:137600; Evidence={ECO:0000269|PubMed:23118010};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000305|PubMed:11007651};
CC Note=Magnesium is required for activity, even if it seems to interact
CC primarily with the substrate. {ECO:0000305};
CC -!- ACTIVITY REGULATION: Is potently inhibited by the sulfone dapsone and
CC the two sulfonamides sulfamethoxazole and sulfamethoxypyridazine, with
CC Kis in the range of 12 to 32 nM. Is only poorly inhibited by p-
CC aminosalicylate (PAS) (PubMed:10542185). The inhibition of DHPS by
CC sulfathiazole antagonizes PAS-mediated growth inhibition and therefore
CC confers resistance to PAS (PubMed:23779105).
CC {ECO:0000269|PubMed:10542185, ECO:0000269|PubMed:23779105}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.37 uM for 4-aminobenzoate {ECO:0000269|PubMed:10542185};
CC KM=1.03 uM for 6-hydroxymethyl-7,8-dihydropterin diphosphate
CC {ECO:0000269|PubMed:10542185};
CC KM=0.6 uM for 4-aminobenzoate {ECO:0000269|PubMed:23118010};
CC KM=1.8 uM for para-aminosalicylate {ECO:0000269|PubMed:23118010};
CC KM=11.4 uM for 4-aminobenzoate {ECO:0000269|PubMed:23779105};
CC KM=17.7 uM for para-aminosalicylate {ECO:0000269|PubMed:23779105};
CC Note=kcat is 35 min(-1) (PubMed:10542185). kcat is 28 min(-1) with
CC pABA as substrate, and 45 min(-1) with PAS as substrate
CC (PubMed:23118010). {ECO:0000269|PubMed:10542185,
CC ECO:0000269|PubMed:23118010};
CC pH dependence:
CC Optimum pH is 8. {ECO:0000269|PubMed:10542185};
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 7,8-
CC dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-
CC dihydropteridine diphosphate and 4-aminobenzoate: step 1/2.
CC {ECO:0000305|PubMed:10542185}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:10542185}.
CC -!- SIMILARITY: Belongs to the DHPS family. {ECO:0000305}.
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DR EMBL; AF117617; AAF06724.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP46431.1; -; Genomic_DNA.
DR PIR; A70956; A70956.
DR RefSeq; WP_003899596.1; NZ_NVQJ01000056.1.
DR RefSeq; YP_177997.1; NC_000962.3.
DR PDB; 1EYE; X-ray; 1.70 A; A=1-280.
DR PDBsum; 1EYE; -.
DR AlphaFoldDB; P9WND1; -.
DR SMR; P9WND1; -.
DR STRING; 83332.Rv3608c; -.
DR DrugBank; DB03592; Pterin-6-Yl-Methyl-Monophosphate.
DR PaxDb; P9WND1; -.
DR DNASU; 885831; -.
DR GeneID; 45427594; -.
DR GeneID; 885831; -.
DR KEGG; mtu:Rv3608c; -.
DR TubercuList; Rv3608c; -.
DR eggNOG; COG0294; Bacteria.
DR OMA; FSIDTYH; -.
DR PhylomeDB; P9WND1; -.
DR BRENDA; 2.5.1.15; 3445.
DR SABIO-RK; P9WND1; -.
DR UniPathway; UPA00077; UER00156.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0004156; F:dihydropteroate synthase activity; IDA:MTBBASE.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046656; P:folic acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IDA:MTBBASE.
DR CDD; cd00739; DHPS; 1.
DR Gene3D; 3.20.20.20; -; 1.
DR InterPro; IPR045031; DHP_synth.
DR InterPro; IPR006390; DHP_synth_dom.
DR InterPro; IPR011005; Dihydropteroate_synth-like.
DR InterPro; IPR000489; Pterin-binding_dom.
DR PANTHER; PTHR20941; PTHR20941; 1.
DR Pfam; PF00809; Pterin_bind; 1.
DR SUPFAM; SSF51717; SSF51717; 1.
DR TIGRFAMs; TIGR01496; DHPS; 1.
DR PROSITE; PS00792; DHPS_1; 1.
DR PROSITE; PS00793; DHPS_2; 1.
DR PROSITE; PS50972; PTERIN_BINDING; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Folate biosynthesis; Magnesium; Metal-binding;
KW Reference proteome; Transferase.
FT CHAIN 1..280
FT /note="Dihydropteroate synthase"
FT /id="PRO_0000168215"
FT DOMAIN 1..265
FT /note="Pterin-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT BINDING 13
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:11007651"
FT BINDING 21
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT BINDING 86
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT BINDING 105
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT BINDING 177
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT BINDING 213
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT BINDING 253..255
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000305|PubMed:11007651,
FT ECO:0007744|PDB:1EYE"
FT STRAND 7..13
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 28..40
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 44..49
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 66..78
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 83..86
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 90..98
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 103..106
FT /evidence="ECO:0007829|PDB:1EYE"
FT TURN 107..110
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 116..123
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 127..130
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 149..166
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 171..173
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 174..177
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 186..194
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 196..200
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 206..208
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 214..219
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 223..225
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 230..233
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 234..246
FT /evidence="ECO:0007829|PDB:1EYE"
FT STRAND 250..255
FT /evidence="ECO:0007829|PDB:1EYE"
FT HELIX 257..271
FT /evidence="ECO:0007829|PDB:1EYE"
SQ SEQUENCE 280 AA; 28843 MW; 737AB6DF12C51C8C CRC64;
MSPAPVQVMG VLNVTDDSFS DGGCYLDLDD AVKHGLAMAA AGAGIVDVGG ESSRPGATRV
DPAVETSRVI PVVKELAAQG ITVSIDTMRA DVARAALQNG AQMVNDVSGG RADPAMGPLL
AEADVPWVLM HWRAVSADTP HVPVRYGNVV AEVRADLLAS VADAVAAGVD PARLVLDPGL
GFAKTAQHNW AILHALPELV ATGIPVLVGA SRKRFLGALL AGPDGVMRPT DGRDTATAVI
SALAALHGAW GVRVHDVRAS VDAIKVVEAW MGAERIERDG
