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Protein

Dihydropteroate synthase

Gene

folP1

Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.3 Publications
Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). PAS is a close structural analog of pABA and acts as an alternative substrate for DHPS, leading to hydroxy-dihydropteroate (H2PtePAS). Metabolomic studies show that PAS, despite its in vitro activity as a competitive inhibitor of DHPS, does not inhibit growth of M.tuberculosis by inhibiting DHPS. PAS exerts its antimycobacterial activity through its effects on M.tuberculosis folate metabolism downstream of DHPS. PAS poisons folate-dependent pathways not only by serving as a replacement substrate for DHPS but also by the products of that reaction serving as replacement substrates and/or inhibitors of subsequent enzymes.2 Publications

Catalytic activityi

6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate.3 Publications
6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminosalicylate = diphosphate + hydroxy-dihydropteroate.1 Publication

Cofactori

Mg2+1 PublicationNote: Magnesium is required for activity, even if it seems to interact primarily with the substrate.Curated

Enzyme regulationi

Is potently inhibited by the sulfone dapsone and the two sulfonamides sulfamethoxazole and sulfamethoxypyridazine, with Kis in the range of 12 to 32 nM. Is only poorly inhibited by p-aminosalicylate (PAS) (PubMed:10542185). The inhibition of DHPS by sulfathiazole antagonizes PAS-mediated growth inhibition and therefore confers resistance to PAS (PubMed:23779105).2 Publications

Kineticsi

kcat is 35 min(-1) (PubMed:10542185). kcat is 28 min(-1) with pABA as substrate, and 45 min(-1) with PAS as substrate (PubMed:23118010).2 Publications

  1. KM=0.37 µM for 4-aminobenzoate1 Publication
  2. KM=1.03 µM for 6-hydroxymethyl-7,8-dihydropterin diphosphate1 Publication
  3. KM=0.6 µM for 4-aminobenzoate1 Publication
  4. KM=1.8 µM for para-aminosalicylate1 Publication
  5. KM=11.4 µM for 4-aminobenzoate1 Publication
  6. KM=17.7 µM for para-aminosalicylate1 Publication

    pH dependencei

    Optimum pH is 8.1 Publication

    Pathwayi: tetrahydrofolate biosynthesis

    This protein is involved in step 1 of the subpathway that synthesizes 7,8-dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate and 4-aminobenzoate.1 Publication
    Proteins known to be involved in the 2 steps of the subpathway in this organism are:
    1. Dihydropteroate synthase (folP1), Dihydropteroate synthase (LH57_19665), Dihydropteroate synthase (LH57_06615)
    2. no protein annotated in this organism
    This subpathway is part of the pathway tetrahydrofolate biosynthesis, which is itself part of Cofactor biosynthesis.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes 7,8-dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate and 4-aminobenzoate, the pathway tetrahydrofolate biosynthesis and in Cofactor biosynthesis.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi13 – 131Magnesium1 Publication
    Binding sitei21 – 2116-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication
    Binding sitei86 – 8616-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication
    Binding sitei105 – 10516-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication
    Binding sitei177 – 17716-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication
    Binding sitei213 – 21316-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication

    GO - Molecular functioni

    • dihydropteroate synthase activity Source: MTBBASE
    • metal ion binding Source: UniProtKB-KW

    GO - Biological processi

    • folic acid biosynthetic process Source: UniProtKB-KW
    • growth Source: MTBBASE
    • tetrahydrofolate biosynthetic process Source: MTBBASE
    Complete GO annotation...

    Keywords - Molecular functioni

    Transferase

    Keywords - Biological processi

    Folate biosynthesis

    Keywords - Ligandi

    Magnesium, Metal-binding

    Enzyme and pathway databases

    UniPathwayiUPA00077; UER00156.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dihydropteroate synthase1 Publication (EC:2.5.1.153 Publications)
    Short name:
    DHPS1 Publication
    Alternative name(s):
    Dihydropteroate pyrophosphorylase
    Gene namesi
    Name:folP1
    Ordered Locus Names:Rv3608c
    ORF Names:MTCY07H7B.14
    OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
    Taxonomic identifieri83332 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
    Proteomesi
    • UP000001584 Componenti: Chromosome

    Organism-specific databases

    TubercuListiRv3608c.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 280280Dihydropteroate synthasePRO_0000168215Add
    BLAST

    Proteomic databases

    PaxDbiP9WND1.

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Protein-protein interaction databases

    STRINGi83332.Rv3608c.

    Structurei

    Secondary structure

    1
    280
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi7 – 137Combined sources
    Helixi28 – 4013Combined sources
    Beta strandi44 – 496Combined sources
    Helixi66 – 7813Combined sources
    Beta strandi83 – 864Combined sources
    Helixi90 – 989Combined sources
    Beta strandi103 – 1064Combined sources
    Turni107 – 1104Combined sources
    Helixi116 – 1238Combined sources
    Beta strandi127 – 1304Combined sources
    Helixi149 – 16618Combined sources
    Helixi171 – 1733Combined sources
    Beta strandi174 – 1774Combined sources
    Helixi186 – 1949Combined sources
    Helixi196 – 2005Combined sources
    Beta strandi206 – 2083Combined sources
    Helixi214 – 2196Combined sources
    Beta strandi223 – 2253Combined sources
    Helixi230 – 2334Combined sources
    Helixi234 – 24613Combined sources
    Beta strandi250 – 2556Combined sources
    Helixi257 – 27115Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1EYEX-ray1.70A1-280[»]
    ProteinModelPortaliP9WND1.
    SMRiP9WND1. Positions 5-274.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini1 – 265265Pterin-bindingPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni253 – 25536-hydroxymethyl-7,8-dihydropterin diphosphate bindingCombined sources1 Publication

    Sequence similaritiesi

    Belongs to the DHPS family.Curated
    Contains 1 pterin-binding domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiENOG4105EEI. Bacteria.
    COG0294. LUCA.
    KOiK00796.
    OMAiSIDTYHA.
    PhylomeDBiP9WND1.

    Family and domain databases

    Gene3Di3.20.20.20. 1 hit.
    InterProiIPR006390. DHP_synth.
    IPR011005. Dihydropteroate_synth-like.
    IPR000489. Pterin-binding_dom.
    [Graphical view]
    PfamiPF00809. Pterin_bind. 1 hit.
    [Graphical view]
    SUPFAMiSSF51717. SSF51717. 1 hit.
    TIGRFAMsiTIGR01496. DHPS. 1 hit.
    PROSITEiPS00792. DHPS_1. 1 hit.
    PS00793. DHPS_2. 1 hit.
    PS50972. PTERIN_BINDING. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P9WND1-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSPAPVQVMG VLNVTDDSFS DGGCYLDLDD AVKHGLAMAA AGAGIVDVGG
    60 70 80 90 100
    ESSRPGATRV DPAVETSRVI PVVKELAAQG ITVSIDTMRA DVARAALQNG
    110 120 130 140 150
    AQMVNDVSGG RADPAMGPLL AEADVPWVLM HWRAVSADTP HVPVRYGNVV
    160 170 180 190 200
    AEVRADLLAS VADAVAAGVD PARLVLDPGL GFAKTAQHNW AILHALPELV
    210 220 230 240 250
    ATGIPVLVGA SRKRFLGALL AGPDGVMRPT DGRDTATAVI SALAALHGAW
    260 270 280
    GVRVHDVRAS VDAIKVVEAW MGAERIERDG
    Length:280
    Mass (Da):28,843
    Last modified:April 16, 2014 - v1
    Checksum:i737AB6DF12C51C8C
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF117617 Genomic DNA. Translation: AAF06724.1.
    AL123456 Genomic DNA. Translation: CCP46431.1.
    PIRiA70956.
    RefSeqiWP_003899596.1. NZ_KK339374.1.
    YP_177997.1. NC_000962.3.

    Genome annotation databases

    EnsemblBacteriaiCCP46431; CCP46431; Rv3608c.
    GeneIDi885831.
    KEGGimtu:Rv3608c.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF117617 Genomic DNA. Translation: AAF06724.1.
    AL123456 Genomic DNA. Translation: CCP46431.1.
    PIRiA70956.
    RefSeqiWP_003899596.1. NZ_KK339374.1.
    YP_177997.1. NC_000962.3.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1EYEX-ray1.70A1-280[»]
    ProteinModelPortaliP9WND1.
    SMRiP9WND1. Positions 5-274.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi83332.Rv3608c.

    Proteomic databases

    PaxDbiP9WND1.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiCCP46431; CCP46431; Rv3608c.
    GeneIDi885831.
    KEGGimtu:Rv3608c.

    Organism-specific databases

    TubercuListiRv3608c.

    Phylogenomic databases

    eggNOGiENOG4105EEI. Bacteria.
    COG0294. LUCA.
    KOiK00796.
    OMAiSIDTYHA.
    PhylomeDBiP9WND1.

    Enzyme and pathway databases

    UniPathwayiUPA00077; UER00156.

    Family and domain databases

    Gene3Di3.20.20.20. 1 hit.
    InterProiIPR006390. DHP_synth.
    IPR011005. Dihydropteroate_synth-like.
    IPR000489. Pterin-binding_dom.
    [Graphical view]
    PfamiPF00809. Pterin_bind. 1 hit.
    [Graphical view]
    SUPFAMiSSF51717. SSF51717. 1 hit.
    TIGRFAMsiTIGR01496. DHPS. 1 hit.
    PROSITEiPS00792. DHPS_1. 1 hit.
    PS00793. DHPS_2. 1 hit.
    PS50972. PTERIN_BINDING. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "Cloning and expression of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase in Escherichia coli."
      Nopponpunth V., Sirawaraporn W., Greene P.J., Santi D.V.
      J. Bacteriol. 181:6814-6821(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, SUBUNIT.
      Strain: H37Rv.
    2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: ATCC 25618 / H37Rv.
    3. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Strain: ATCC 25618 / H37Rv.
    4. "para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis."
      Zheng J., Rubin E.J., Bifani P., Mathys V., Lim V., Au M., Jang J., Nam J., Dick T., Walker J.R., Pethe K., Camacho L.R.
      J. Biol. Chem. 288:23447-23456(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION.
      Strain: H37Rv.
    5. "Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis."
      Chakraborty S., Gruber T., Barry C.E. III, Boshoff H.I., Rhee K.Y.
      Science 339:88-91(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
      Strain: H37Rv.
    6. "Crystal structure of Mycobacterium tuberculosis 7,8-dihydropteroate synthase in complex with pterin monophosphate: new insight into the enzymatic mechanism and sulfa-drug action."
      Baca A.M., Sirawaraporn R., Turley S., Sirawaraporn W., Hol W.G.J.
      J. Mol. Biol. 302:1193-1212(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) IN COMPLEX WITH MAGNESIUM IONS AND PTERIN MONOPHOSPHATE, COFACTOR.
    7. Erratum
      Baca A.M., Sirawaraporn R., Turley S., Sirawaraporn W., Hol W.G.J.
      J. Mol. Biol. 303:843-843(2000)

    Entry informationi

    Entry nameiDHPS1_MYCTU
    AccessioniPrimary (citable) accession number: P9WND1
    Secondary accession number(s): L0TG01, O06274, P0A578
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 16, 2014
    Last sequence update: April 16, 2014
    Last modified: January 20, 2016
    This is version 18 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh
      Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh: entries and gene names
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.