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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

Manual assertion based on experiment ini

  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)DescriptionActionsGraphical viewLength
    Metal bindingi13Magnesium1 Publication1
    Binding sitei216-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication1
    Binding sitei866-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication1
    Binding sitei1056-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication1
    Binding sitei1776-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication1
    Binding sitei2136-hydroxymethyl-7,8-dihydropterin diphosphateCombined sources1 Publication1

    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

    BioCyciMTBH37RV:G185E-7887-MONOMER.
    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)DescriptionActionsGraphical viewLength
    ChainiPRO_00001682151 – 280Dihydropteroate synthaseAdd BLAST280

    Proteomic databases

    PaxDbiP9WND1.

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Protein-protein interaction databases

    STRINGi83332.Rv3608c.

    Structurei

    Secondary structure

    1280
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi7 – 13Combined sources7
    Helixi28 – 40Combined sources13
    Beta strandi44 – 49Combined sources6
    Helixi66 – 78Combined sources13
    Beta strandi83 – 86Combined sources4
    Helixi90 – 98Combined sources9
    Beta strandi103 – 106Combined sources4
    Turni107 – 110Combined sources4
    Helixi116 – 123Combined sources8
    Beta strandi127 – 130Combined sources4
    Helixi149 – 166Combined sources18
    Helixi171 – 173Combined sources3
    Beta strandi174 – 177Combined sources4
    Helixi186 – 194Combined sources9
    Helixi196 – 200Combined sources5
    Beta strandi206 – 208Combined sources3
    Helixi214 – 219Combined sources6
    Beta strandi223 – 225Combined sources3
    Helixi230 – 233Combined sources4
    Helixi234 – 246Combined sources13
    Beta strandi250 – 255Combined sources6
    Helixi257 – 271Combined sources15

    3D structure databases

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

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini1 – 265Pterin-bindingPROSITE-ProRule annotationAdd BLAST265

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni253 – 2556-hydroxymethyl-7,8-dihydropterin diphosphate bindingCombined sources1 Publication3

    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

    CDDicd00739. DHPS. 1 hit.
    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
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1EYEX-ray1.70A1-280[»]
    ProteinModelPortaliP9WND1.
    SMRiP9WND1.
    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.
    BioCyciMTBH37RV:G185E-7887-MONOMER.

    Family and domain databases

    CDDicd00739. DHPS. 1 hit.
    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...

    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: November 30, 2016
    This is version 20 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.