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Protein

Thymidylate synthase ThyA

Gene

thyA

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 reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP) while utilizing 5,10-methylenetetrahydrofolate (mTHF) as the methyl donor and reductant in the reaction, yielding dihydrofolate (DHF) as a by-product. This enzymatic reaction provides an intracellular de novo source of dTMP, an essential precursor for DNA biosynthesis.1 Publication

Catalytic activityi

5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP.UniRule annotation1 Publication

Enzyme regulationi

Is potently inhibited by 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), and by the folate-based 1843U89.1 Publication

Kineticsi

kcat is 18 min(-1).1 Publication

Manual assertion based on experiment ini

  1. KM=4 µM for dUMP1 Publication
  2. KM=70 µM for 5,10-methylenetetrahydrofolate1 Publication

    Pathwayi: dTTP biosynthesis

    This protein is involved in the pathway dTTP biosynthesis, which is part of Pyrimidine metabolism.UniRule annotation
    View all proteins of this organism that are known to be involved in the pathway dTTP biosynthesis and in Pyrimidine metabolism.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei21dUMPCombined sources1 Publication1
    Binding sitei515,10-methylenetetrahydrofolateCombined sources1 Publication1
    Active sitei146NucleophileUniRule annotation1
    Binding sitei1695,10-methylenetetrahydrofolateCombined sources1 Publication1
    Binding sitei177dUMPCombined sources1 Publication1
    Binding sitei2625,10-methylenetetrahydrofolate; via carbonyl oxygenCombined sources1 Publication1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi126 – 127dUMP; shared with dimeric partnerCombined sources1 Publication2
    Nucleotide bindingi166 – 169dUMPCombined sources1 Publication4
    Nucleotide bindingi207 – 209dUMPCombined sources1 Publication3

    GO - Molecular functioni

    • thymidylate synthase activity Source: MTBBASE

    GO - Biological processi

    • dTMP biosynthetic process Source: MTBBASE
    • dTTP biosynthetic process Source: UniProtKB-UniPathway
    • dUMP catabolic process Source: MTBBASE
    • response to antibiotic Source: UniProtKB-KW
    Complete GO annotation...

    Keywords - Molecular functioni

    Methyltransferase, Transferase

    Keywords - Biological processi

    Antibiotic resistance, Nucleotide biosynthesis

    Enzyme and pathway databases

    BioCyciMetaCyc:G185E-7013-MONOMER.
    MTBH37RV:G185E-7013-MONOMER.
    UniPathwayiUPA00575.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Thymidylate synthase ThyA1 Publication (EC:2.1.1.45UniRule annotation1 Publication)
    Short name:
    TS1 PublicationUniRule annotation
    Short name:
    TSaseUniRule annotation
    Gene namesi
    Name:thyAUniRule annotation
    Ordered Locus Names:Rv2764c
    ORF Names:MTV002.29c
    OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
    Taxonomic identifieri83332 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
    Proteomesi
    • UP000001584 Componenti: Chromosome

    Organism-specific databases

    TubercuListiRv2764c.

    Subcellular locationi

    • Cytoplasm UniRule annotation

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Disruption phenotypei

    Cells lacking this gene display an in vitro growth defect, but deletion of thyA does not affect M.tuberculosis in vivo growth. Moreover, thyA deletion confers PAS resistance.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi202T → A: Appears to be functional by complementation study. 1 Publication1
    Mutagenesisi261V → A: Appears to be non-functional by complementation study. 1 Publication1

    Chemistry databases

    ChEMBLiCHEMBL1795162.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001409901 – 263Thymidylate synthase ThyAAdd BLAST263

    Proteomic databases

    PaxDbiP9WFR9.

    Expressioni

    Inductioni

    Is expressed under the exponential phase of growth, and down-regulated upon reaching the stationary phase or under both oxidative and nitrosative stress. Expression of thyA is significantly increased within murine macrophages or under acid stress. Is expressed at a higher level than thyX under all of the in vitro and in vivo growth conditions tested.1 Publication

    Interactioni

    Subunit structurei

    Homodimer.UniRule annotation1 Publication

    Protein-protein interaction databases

    STRINGi83332.Rv2764c.

    Chemistry databases

    BindingDBiP9WFR9.

    Structurei

    Secondary structure

    1263
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi3 – 14Combined sources12
    Beta strandi16 – 18Combined sources3
    Beta strandi21 – 23Combined sources3
    Beta strandi26 – 37Combined sources12
    Helixi38 – 40Combined sources3
    Turni46 – 49Combined sources4
    Helixi52 – 64Combined sources13
    Helixi70 – 74Combined sources5
    Helixi81 – 83Combined sources3
    Helixi94 – 100Combined sources7
    Helixi111 – 121Combined sources11
    Beta strandi129 – 131Combined sources3
    Turni135 – 137Combined sources3
    Helixi138 – 140Combined sources3
    Beta strandi141 – 143Combined sources3
    Beta strandi146 – 155Combined sources10
    Beta strandi158 – 169Combined sources12
    Turni170 – 172Combined sources3
    Helixi173 – 192Combined sources20
    Beta strandi195 – 209Combined sources15
    Helixi210 – 212Combined sources3
    Helixi213 – 220Combined sources8
    Beta strandi229 – 232Combined sources4
    Helixi238 – 240Combined sources3
    Helixi243 – 245Combined sources3
    Beta strandi246 – 250Combined sources5

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3QJ7X-ray2.50A/B/C/D1-263[»]
    4FOAX-ray2.25A/B/C/D1-263[»]
    4FOGX-ray2.40A/B/C/D1-263[»]
    4FOXX-ray2.30A/B/C/D/E/F/G/H1-263[»]
    4FQSX-ray1.80A/B1-263[»]
    ProteinModelPortaliP9WFR9.
    SMRiP9WFR9.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the thymidylate synthase family. Bacterial-type ThyA subfamily.UniRule annotation

    Phylogenomic databases

    eggNOGiENOG4105C0V. Bacteria.
    COG0207. LUCA.
    KOiK00560.
    OMAiIVYELLW.
    PhylomeDBiP9WFR9.

    Family and domain databases

    CDDicd00351. TS_Pyrimidine_HMase. 1 hit.
    Gene3Di3.30.572.10. 1 hit.
    HAMAPiMF_00008. Thymidy_synth_bact. 1 hit.
    InterProiIPR023451. Thymidate_synth/dCMP_Mease.
    IPR000398. Thymidylate_synthase.
    IPR020940. Thymidylate_synthase_AS.
    [Graphical view]
    PfamiPF00303. Thymidylat_synt. 1 hit.
    [Graphical view]
    PRINTSiPR00108. THYMDSNTHASE.
    SUPFAMiSSF55831. SSF55831. 1 hit.
    TIGRFAMsiTIGR03284. thym_sym. 2 hits.
    PROSITEiPS00091. THYMIDYLATE_SYNTHASE. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P9WFR9-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MTPYEDLLRF VLETGTPKSD RTGTGTRSLF GQQMRYDLSA GFPLLTTKKV
    60 70 80 90 100
    HFKSVAYELL WFLRGDSNIG WLHEHGVTIW DEWASDTGEL GPIYGVQWRS
    110 120 130 140 150
    WPAPSGEHID QISAALDLLR TDPDSRRIIV SAWNVGEIER MALPPCHAFF
    160 170 180 190 200
    QFYVADGRLS CQLYQRSADL FLGVPFNIAS YALLTHMMAA QAGLSVGEFI
    210 220 230 240 250
    WTGGDCHIYD NHVEQVRLQL SREPRPYPKL LLADRDSIFE YTYEDIVVKN
    260
    YDPHPAIKAP VAV
    Length:263
    Mass (Da):29,853
    Last modified:April 16, 2014 - v1
    Checksum:iDF48279E3E9EA5F3
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP45563.1.
    PIRiC70881.
    RefSeqiNP_217280.1. NC_000962.3.
    WP_003414075.1. NC_000962.3.

    Genome annotation databases

    EnsemblBacteriaiCCP45563; CCP45563; Rv2764c.
    GeneIDi887728.
    KEGGimtu:Rv2764c.
    mtv:RVBD_2764c.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP45563.1.
    PIRiC70881.
    RefSeqiNP_217280.1. NC_000962.3.
    WP_003414075.1. NC_000962.3.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3QJ7X-ray2.50A/B/C/D1-263[»]
    4FOAX-ray2.25A/B/C/D1-263[»]
    4FOGX-ray2.40A/B/C/D1-263[»]
    4FOXX-ray2.30A/B/C/D/E/F/G/H1-263[»]
    4FQSX-ray1.80A/B1-263[»]
    ProteinModelPortaliP9WFR9.
    SMRiP9WFR9.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi83332.Rv2764c.

    Chemistry databases

    BindingDBiP9WFR9.
    ChEMBLiCHEMBL1795162.

    Proteomic databases

    PaxDbiP9WFR9.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiCCP45563; CCP45563; Rv2764c.
    GeneIDi887728.
    KEGGimtu:Rv2764c.
    mtv:RVBD_2764c.

    Organism-specific databases

    TubercuListiRv2764c.

    Phylogenomic databases

    eggNOGiENOG4105C0V. Bacteria.
    COG0207. LUCA.
    KOiK00560.
    OMAiIVYELLW.
    PhylomeDBiP9WFR9.

    Enzyme and pathway databases

    UniPathwayiUPA00575.
    BioCyciMetaCyc:G185E-7013-MONOMER.
    MTBH37RV:G185E-7013-MONOMER.

    Family and domain databases

    CDDicd00351. TS_Pyrimidine_HMase. 1 hit.
    Gene3Di3.30.572.10. 1 hit.
    HAMAPiMF_00008. Thymidy_synth_bact. 1 hit.
    InterProiIPR023451. Thymidate_synth/dCMP_Mease.
    IPR000398. Thymidylate_synthase.
    IPR020940. Thymidylate_synthase_AS.
    [Graphical view]
    PfamiPF00303. Thymidylat_synt. 1 hit.
    [Graphical view]
    PRINTSiPR00108. THYMDSNTHASE.
    SUPFAMiSSF55831. SSF55831. 1 hit.
    TIGRFAMsiTIGR03284. thym_sym. 2 hits.
    PROSITEiPS00091. THYMIDYLATE_SYNTHASE. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiTYSY_MYCTU
    AccessioniPrimary (citable) accession number: P9WFR9
    Secondary accession number(s): L0TD99, O33306, P67044
    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

    Miscellaneous

    Mutations within this gene have been associated with resistance to p-aminosalicylic acid (PAS) in some PAS-resistant M.tuberculosis clinical isolates and spontaneous mutants (PubMed:19237648) (PubMed:15225321). It seems that functional ThyA is required for M.tuberculosis to be sensitive to PAS (PubMed:22034487).1 Publication2 Publications

    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.