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Protein

Flavin-dependent thymidylate synthase

Gene

thyX

Organism
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
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 NAD(P)H and FADH2 as the reductant.2 Publications

Catalytic activityi

5,10-methylenetetrahydrofolate + dUMP + NADPH = dTMP + tetrahydrofolate + NADP+.2 Publications

Cofactori

FAD1 Publication1 PublicationNote: Binds 4 FAD per tetramer. Each FAD binding site is formed by three monomers.2 Publications

Kineticsi

kcat is 1.2 sec(-1) (at 65 degrees Celsius).1 Publication

Manual assertion based on experiment ini

  1. KM=30 µM for dUMP (at 65 degrees Celsius)1 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 sitei55FAD; shared with neighboring subunitsCombined sources6 Publications1
    Binding sitei86FAD; shared with neighboring subunitsCombined sources7 Publications1
    Binding sitei147dUMPCombined sources6 Publications1
    Binding sitei169FADCombined sources7 Publications1
    Active sitei174Involved in ionization of N3 of dUMP, leading to its activation1 Publication1
    Binding sitei174dUMP; shared with dimeric partnerCombined sources6 Publications1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi75 – 78dUMP; shared with dimeric partnerCombined sources6 Publications4
    Nucleotide bindingi78 – 81FADCombined sources7 Publications4
    Nucleotide bindingi86 – 90dUMPCombined sources6 Publications5
    Nucleotide bindingi163 – 165FAD; shared with neighboring subunitsCombined sources7 Publications3

    GO - Molecular functioni

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Methyltransferase, Transferase

    Keywords - Biological processi

    Nucleotide biosynthesis

    Keywords - Ligandi

    FAD, Flavoprotein, NAD, NADP

    Enzyme and pathway databases

    BioCyciMetaCyc:MONOMER-15758.
    BRENDAi2.1.1.148. 2604.
    SABIO-RKQ9WYT0.
    UniPathwayiUPA00575.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Flavin-dependent thymidylate synthase4 Publications (EC:2.1.1.1482 Publications)
    Short name:
    FDTS4 Publications
    Alternative name(s):
    FAD-dependent thymidylate synthaseUniRule annotation
    Thymidylate synthase ThyXUniRule annotation
    Short name:
    TSUniRule annotation
    Short name:
    TSaseUniRule annotation
    Gene namesi
    Name:thyX1 Publication
    Synonyms:thy11 Publication
    Ordered Locus Names:TM_0449
    OrganismiThermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
    Taxonomic identifieri243274 [NCBI]
    Taxonomic lineageiBacteriaThermotogaeThermotogalesThermotogaceaeThermotoga
    Proteomesi
    • UP000008183 Componenti: Chromosome

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi53H → A: Shows 1.39% of wild-type activity. 1 Publication1
    Mutagenesisi88S → A or C: Still catalytically active although shows a large decrease in activity. 1 Publication1
    Mutagenesisi90R → A: Binds dUMP 670-fold weaker than wild-type. 1 Publication1
    Mutagenesisi144E → A: Shows 0.113% of wild-type activity. 1 Publication1
    Mutagenesisi144E → R: Shows 0.016% of wild-type activity. 1 Publication1
    Mutagenesisi174R → A: Still catalytically active although only shows 0.0008% of wild-type activity. Binds dUMP 7300-fold weaker than wild-type. 2 Publications1
    Mutagenesisi174R → K: Loss of catalytic activity. 1 Publication1

    Chemistry databases

    DrugBankiDB03147. Flavin adenine dinucleotide.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001755791 – 220Flavin-dependent thymidylate synthaseAdd BLAST220

    Interactioni

    Subunit structurei

    Homotetramer.3 Publications

    Protein-protein interaction databases

    DIPiDIP-60076N.
    STRINGi243274.TM0449.

    Structurei

    Secondary structure

    1220
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi2 – 5Combined sources4
    Turni6 – 8Combined sources3
    Beta strandi9 – 17Combined sources9
    Helixi20 – 28Combined sources9
    Helixi29 – 31Combined sources3
    Helixi39 – 51Combined sources13
    Helixi55 – 59Combined sources5
    Beta strandi61 – 69Combined sources9
    Helixi70 – 76Combined sources7
    Beta strandi81 – 86Combined sources6
    Turni89 – 91Combined sources3
    Helixi103 – 106Combined sources4
    Helixi115 – 138Combined sources24
    Helixi143 – 146Combined sources4
    Helixi147 – 149Combined sources3
    Beta strandi154 – 163Combined sources10
    Helixi164 – 174Combined sources11
    Helixi181 – 197Combined sources17
    Helixi199 – 208Combined sources10
    Helixi214 – 216Combined sources3

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1KQ4X-ray2.25A/B/C/D1-220[»]
    1O24X-ray2.00A/B/C/D1-220[»]
    1O25X-ray2.40A/B/C/D1-220[»]
    1O26X-ray1.60A/B/C/D1-220[»]
    1O27X-ray2.30A/B/C/D1-220[»]
    1O28X-ray2.10A/B/C/D1-220[»]
    1O29X-ray2.00A/B/C/D1-220[»]
    1O2AX-ray1.80A/B/C/D1-220[»]
    1O2BX-ray2.45A/B/C/D1-220[»]
    3G4AX-ray1.95A/B/C/D1-220[»]
    3G4CX-ray2.05A/B/C/D1-220[»]
    3N0BX-ray2.30A/B/C/D1-220[»]
    3N0CX-ray2.30A/B/C/D1-220[»]
    4GT9X-ray1.39A1-220[»]
    4GTAX-ray1.50A1-220[»]
    4GTBX-ray1.70A1-220[»]
    4GTCX-ray1.97A/B/C/D1-220[»]
    4GTDX-ray1.76A/B/C/D1-220[»]
    4GTEX-ray1.89A/B/C/D1-220[»]
    4GTFX-ray1.77A1-220[»]
    4GTLX-ray2.17A/B/C/D1-220[»]
    4KARX-ray2.03A/B/C/D1-220[»]
    4KASX-ray1.85A/B/C/D1-220[»]
    4KATX-ray2.14A/B/C/D1-220[»]
    5CHPX-ray1.70A1-220[»]
    5IOQX-ray1.93A/B/C/D1-220[»]
    5IORX-ray1.95A1-220[»]
    5IOSX-ray1.90A/B/C/D1-220[»]
    5IOTX-ray2.00A/B/C/D1-220[»]
    ProteinModelPortaliQ9WYT0.
    SMRiQ9WYT0.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9WYT0.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini1 – 208ThyXUniRule annotationAdd BLAST208

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi78 – 88ThyX motifUniRule annotationAdd BLAST11

    Sequence similaritiesi

    Belongs to the thymidylate synthase ThyX family.UniRule annotation
    Contains 1 thyX (flavin-dependent thymidylate synthase) domain.UniRule annotation

    Phylogenomic databases

    eggNOGiENOG41087GE. Bacteria.
    COG1351. LUCA.
    InParanoidiQ9WYT0.
    KOiK03465.
    OMAiGMTKREW.

    Family and domain databases

    HAMAPiMF_01408. ThyX. 1 hit.
    InterProiIPR003669. Thymidylate_synthase_ThyX.
    [Graphical view]
    PfamiPF02511. Thy1. 1 hit.
    [Graphical view]
    SUPFAMiSSF69796. SSF69796. 1 hit.
    TIGRFAMsiTIGR02170. thyX. 1 hit.
    PROSITEiPS51331. THYX. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q9WYT0-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MKIDILDKGF VELVDVMGND LSAVRAARVS FDMGLKDEER DRHLIEYLMK
    60 70 80 90 100
    HGHETPFEHI VFTFHVKAPI FVARQWFRHR IASYNELSGR YSKLSYEFYI
    110 120 130 140 150
    PSPERLEGYK TTIPPERVTE KISEIVDKAY RTYLELIESG VPREVARIVL
    160 170 180 190 200
    PLNLYTRFFW TVNARSLMNF LNLRADSHAQ WEIQQYALAI ARIFKEKCPW
    210 220
    TFEAFLKYAY KGDILKEVQV
    Length:220
    Mass (Da):26,004
    Last modified:November 1, 1999 - v1
    Checksum:iE3B9712014185907
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AE000512 Genomic DNA. Translation: AAD35532.1.
    PIRiB72375.
    RefSeqiNP_228259.1. NC_000853.1.
    WP_004081517.1. NZ_CP011107.1.

    Genome annotation databases

    EnsemblBacteriaiAAD35532; AAD35532; TM_0449.
    GeneIDi897468.
    KEGGitma:TM0449.
    PATRICi23935783. VBITheMar51294_0455.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AE000512 Genomic DNA. Translation: AAD35532.1.
    PIRiB72375.
    RefSeqiNP_228259.1. NC_000853.1.
    WP_004081517.1. NZ_CP011107.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1KQ4X-ray2.25A/B/C/D1-220[»]
    1O24X-ray2.00A/B/C/D1-220[»]
    1O25X-ray2.40A/B/C/D1-220[»]
    1O26X-ray1.60A/B/C/D1-220[»]
    1O27X-ray2.30A/B/C/D1-220[»]
    1O28X-ray2.10A/B/C/D1-220[»]
    1O29X-ray2.00A/B/C/D1-220[»]
    1O2AX-ray1.80A/B/C/D1-220[»]
    1O2BX-ray2.45A/B/C/D1-220[»]
    3G4AX-ray1.95A/B/C/D1-220[»]
    3G4CX-ray2.05A/B/C/D1-220[»]
    3N0BX-ray2.30A/B/C/D1-220[»]
    3N0CX-ray2.30A/B/C/D1-220[»]
    4GT9X-ray1.39A1-220[»]
    4GTAX-ray1.50A1-220[»]
    4GTBX-ray1.70A1-220[»]
    4GTCX-ray1.97A/B/C/D1-220[»]
    4GTDX-ray1.76A/B/C/D1-220[»]
    4GTEX-ray1.89A/B/C/D1-220[»]
    4GTFX-ray1.77A1-220[»]
    4GTLX-ray2.17A/B/C/D1-220[»]
    4KARX-ray2.03A/B/C/D1-220[»]
    4KASX-ray1.85A/B/C/D1-220[»]
    4KATX-ray2.14A/B/C/D1-220[»]
    5CHPX-ray1.70A1-220[»]
    5IOQX-ray1.93A/B/C/D1-220[»]
    5IORX-ray1.95A1-220[»]
    5IOSX-ray1.90A/B/C/D1-220[»]
    5IOTX-ray2.00A/B/C/D1-220[»]
    ProteinModelPortaliQ9WYT0.
    SMRiQ9WYT0.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    DIPiDIP-60076N.
    STRINGi243274.TM0449.

    Chemistry databases

    DrugBankiDB03147. Flavin adenine dinucleotide.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiAAD35532; AAD35532; TM_0449.
    GeneIDi897468.
    KEGGitma:TM0449.
    PATRICi23935783. VBITheMar51294_0455.

    Phylogenomic databases

    eggNOGiENOG41087GE. Bacteria.
    COG1351. LUCA.
    InParanoidiQ9WYT0.
    KOiK03465.
    OMAiGMTKREW.

    Enzyme and pathway databases

    UniPathwayiUPA00575.
    BioCyciMetaCyc:MONOMER-15758.
    BRENDAi2.1.1.148. 2604.
    SABIO-RKQ9WYT0.

    Miscellaneous databases

    EvolutionaryTraceiQ9WYT0.

    Family and domain databases

    HAMAPiMF_01408. ThyX. 1 hit.
    InterProiIPR003669. Thymidylate_synthase_ThyX.
    [Graphical view]
    PfamiPF02511. Thy1. 1 hit.
    [Graphical view]
    SUPFAMiSSF69796. SSF69796. 1 hit.
    TIGRFAMsiTIGR02170. thyX. 1 hit.
    PROSITEiPS51331. THYX. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiTHYX_THEMA
    AccessioniPrimary (citable) accession number: Q9WYT0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 11, 2001
    Last sequence update: November 1, 1999
    Last modified: November 30, 2016
    This is version 118 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Reaction mechanism involved a direct methylene transfer from mTHF to dUMP (PubMed:23019356). FDTS ionizes N3 of dUMP using the active-site Arg-174, providing a new mechanism for dUMP activation. The phosphate of dUMP is crucial for flavin oxidation, suggesting that it acts as the base that deprotonates C5 of the dUMP-methylene adduct (PubMed:27214228).2 Publications

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. 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.