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Protein

Serine hydroxymethyltransferase, mitochondrial

Gene

SHMT2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism. Thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Interconversion of serine and glycine (PubMed:25619277). Associates with mitochondrial DNA (PubMed:18063578). Plays a role in the deubiquitination of target proteins as component of the BRISC complex (PubMed:24075985). Required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985).4 Publications

Catalytic activityi

5,10-methylenetetrahydrofolate + glycine + H2O = tetrahydrofolate + L-serine.2 Publications

Cofactori

pyridoxal 5'-phosphate1 Publication

Kineticsi

  1. KM=278 µM for L-serine1 Publication
  2. KM=23 µM for tetrahydrofolate1 Publication

    Pathwayi: tetrahydrofolate interconversion

    This protein is involved in the pathway tetrahydrofolate interconversion, which is part of One-carbon metabolism.1 Publication
    View all proteins of this organism that are known to be involved in the pathway tetrahydrofolate interconversion and in One-carbon metabolism.

    GO - Molecular functioni

    • amino acid binding Source: Ensembl
    • chromatin binding Source: UniProtKB
    • glycine hydroxymethyltransferase activity Source: UniProtKB
    • L-allo-threonine aldolase activity Source: Ensembl
    • pyridoxal phosphate binding Source: UniProtKB

    GO - Biological processi

    • folic acid metabolic process Source: Reactome
    • glycine biosynthetic process from serine Source: Ensembl
    • glycine metabolic process Source: UniProtKB
    • L-serine biosynthetic process Source: Ensembl
    • L-serine metabolic process Source: UniProtKB
    • one-carbon metabolic process Source: UniProtKB
    • positive regulation of cell proliferation Source: Ensembl
    • protein homotetramerization Source: Ensembl
    • protein K63-linked deubiquitination Source: UniProtKB
    • protein tetramerization Source: UniProtKB
    • response to type I interferon Source: UniProtKB
    • tetrahydrofolate interconversion Source: UniProtKB-UniPathway
    • tetrahydrofolate metabolic process Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Transferase

    Keywords - Biological processi

    One-carbon metabolism

    Keywords - Ligandi

    Pyridoxal phosphate

    Enzyme and pathway databases

    BioCyciMetaCyc:HS00049-MONOMER.
    ZFISH:HS00049-MONOMER.
    ReactomeiR-HSA-196757. Metabolism of folate and pterines.
    UniPathwayiUPA00193.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine hydroxymethyltransferase, mitochondrial (EC:2.1.2.12 Publications)
    Short name:
    SHMT
    Alternative name(s):
    Glycine hydroxymethyltransferase
    Serine methylase
    Gene namesi
    Name:SHMT2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 12

    Organism-specific databases

    HGNCiHGNC:10852. SHMT2.

    Subcellular locationi

    GO - Cellular componenti

    • BRISC complex Source: UniProtKB
    • cytoplasm Source: BHF-UCL
    • extracellular exosome Source: UniProtKB
    • microtubule cytoskeleton Source: HPA
    • mitochondrial inner membrane Source: UniProtKB
    • mitochondrial intermembrane space Source: Ensembl
    • mitochondrial matrix Source: UniProtKB
    • mitochondrial nucleoid Source: BHF-UCL
    • mitochondrion Source: BHF-UCL
    • nucleus Source: BHF-UCL
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Mitochondrion, Mitochondrion inner membrane, Mitochondrion nucleoid, Nucleus

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi6472.
    OpenTargetsiENSG00000182199.
    PharmGKBiPA35755.

    Chemistry databases

    DrugBankiDB00145. Glycine.
    DB00116. Tetrahydrofolic acid.

    Polymorphism and mutation databases

    BioMutaiSHMT2.
    DMDMi6226865.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 29MitochondrionAdd BLAST29
    ChainiPRO_000003256230 – 504Serine hydroxymethyltransferase, mitochondrialAdd BLAST475

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei103N6-acetyllysineCombined sources1
    Modified residuei181N6-acetyllysineCombined sources1
    Modified residuei196N6-acetyllysineCombined sources1
    Modified residuei280N6-(pyridoxal phosphate)lysineBy similarity1
    Modified residuei297N6-acetyllysineCombined sources1
    Modified residuei356N6-acetyllysineCombined sources1
    Modified residuei464N6-acetyllysineCombined sources1
    Modified residuei469N6-acetyllysineCombined sources1
    Modified residuei470PhosphoserineCombined sources1
    Modified residuei474N6-acetyllysineCombined sources1

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiP34897.
    PaxDbiP34897.
    PeptideAtlasiP34897.
    PRIDEiP34897.

    PTM databases

    iPTMnetiP34897.
    PhosphoSitePlusiP34897.
    SwissPalmiP34897.

    Expressioni

    Gene expression databases

    BgeeiENSG00000182199.
    CleanExiHS_SHMT2.
    ExpressionAtlasiP34897. baseline and differential.
    GenevisibleiP34897. HS.

    Organism-specific databases

    HPAiHPA020543.
    HPA020549.

    Interactioni

    Subunit structurei

    Homotetramer; in the presence of bound pyridoxal 5'-phosphate. Homodimer; in the absence of bound pyridoxal 5'-phosphate. Pyridoxal 5'-phosphate binding mediates an important conformation change that is required for tetramerization (PubMed:25619277). Interacts with FAM175B; the interaction is direct. Identified in a complex with FAM175B and the other subunits of the BRISC complex, at least composed of the FAM175B/ABRO1, BRCC3/BRCC36, BRE/BRCC45 and BABAM1/NBA1. Identified in a complex with FAM175B and INAR1 (PubMed:24075985). Interacts with KIRREL3 (PubMed:25902260).3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ARL6IP1Q150413EBI-352908,EBI-714543
    CMTM5Q96DZ93EBI-352908,EBI-2548702

    Protein-protein interaction databases

    BioGridi112368. 432 interactors.
    IntActiP34897. 34 interactors.
    MINTiMINT-3013548.
    STRINGi9606.ENSP00000333667.

    Structurei

    Secondary structure

    1504
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi49 – 52Combined sources4
    Helixi54 – 69Combined sources16
    Beta strandi70 – 72Combined sources3
    Helixi82 – 88Combined sources7
    Helixi91 – 93Combined sources3
    Beta strandi103 – 107Combined sources5
    Helixi111 – 126Combined sources16
    Turni131 – 133Combined sources3
    Beta strandi134 – 137Combined sources4
    Helixi143 – 154Combined sources12
    Beta strandi160 – 164Combined sources5
    Helixi166 – 168Combined sources3
    Helixi172 – 174Combined sources3
    Helixi186 – 189Combined sources4
    Beta strandi190 – 195Combined sources6
    Turni199 – 201Combined sources3
    Beta strandi202 – 204Combined sources3
    Helixi206 – 216Combined sources11
    Beta strandi219 – 223Combined sources5
    Helixi234 – 244Combined sources11
    Beta strandi247 – 251Combined sources5
    Helixi253 – 255Combined sources3
    Helixi256 – 260Combined sources5
    Helixi267 – 269Combined sources3
    Beta strandi272 – 280Combined sources9
    Beta strandi288 – 293Combined sources6
    Beta strandi295 – 299Combined sources5
    Beta strandi306 – 308Combined sources3
    Helixi312 – 319Combined sources8
    Turni320 – 323Combined sources4
    Helixi329 – 343Combined sources15
    Helixi345 – 367Combined sources23
    Helixi373 – 375Combined sources3
    Beta strandi378 – 385Combined sources8
    Helixi387 – 389Combined sources3
    Helixi393 – 402Combined sources10
    Beta strandi408 – 410Combined sources3
    Beta strandi418 – 420Combined sources3
    Beta strandi422 – 428Combined sources7
    Helixi429 – 433Combined sources5
    Helixi438 – 460Combined sources23
    Helixi465 – 474Combined sources10
    Helixi476 – 493Combined sources18

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3OU5X-ray2.04A17-504[»]
    4PVFX-ray2.60A/B22-504[»]
    ProteinModelPortaliP34897.
    SMRiP34897.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP34897.

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the SHMT family.Curated

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2467. Eukaryota.
    COG0112. LUCA.
    GeneTreeiENSGT00390000002762.
    HOGENOMiHOG000239405.
    HOVERGENiHBG002807.
    InParanoidiP34897.
    KOiK00600.
    OMAiMAIRCQH.
    OrthoDBiEOG091G05AU.
    PhylomeDBiP34897.
    TreeFamiTF314667.

    Family and domain databases

    CDDicd00378. SHMT. 1 hit.
    Gene3Di3.40.640.10. 1 hit.
    3.90.1150.10. 1 hit.
    HAMAPiMF_00051. SHMT. 1 hit.
    InterProiIPR015424. PyrdxlP-dep_Trfase.
    IPR015421. PyrdxlP-dep_Trfase_major_sub1.
    IPR015422. PyrdxlP-dep_Trfase_major_sub2.
    IPR001085. Ser_HO-MeTrfase.
    IPR019798. Ser_HO-MeTrfase_PLP_BS.
    [Graphical view]
    PANTHERiPTHR11680. PTHR11680. 1 hit.
    PfamiPF00464. SHMT. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000412. SHMT. 1 hit.
    SUPFAMiSSF53383. SSF53383. 1 hit.
    PROSITEiPS00096. SHMT. 1 hit.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P34897-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MLYFSLFWAA RPLQRCGQLV RMAIRAQHSN AAQTQTGEAN RGWTGQESLS
    60 70 80 90 100
    DSDPEMWELL QREKDRQCRG LELIASENFC SRAALEALGS CLNNKYSEGY
    110 120 130 140 150
    PGKRYYGGAE VVDEIELLCQ RRALEAFDLD PAQWGVNVQP YSGSPANLAV
    160 170 180 190 200
    YTALLQPHDR IMGLDLPDGG HLTHGYMSDV KRISATSIFF ESMPYKLNPK
    210 220 230 240 250
    TGLIDYNQLA LTARLFRPRL IIAGTSAYAR LIDYARMREV CDEVKAHLLA
    260 270 280 290 300
    DMAHISGLVA AKVIPSPFKH ADIVTTTTHK TLRGARSGLI FYRKGVKAVD
    310 320 330 340 350
    PKTGREIPYT FEDRINFAVF PSLQGGPHNH AIAAVAVALK QACTPMFREY
    360 370 380 390 400
    SLQVLKNARA MADALLERGY SLVSGGTDNH LVLVDLRPKG LDGARAERVL
    410 420 430 440 450
    ELVSITANKN TCPGDRSAIT PGGLRLGAPA LTSRQFREDD FRRVVDFIDE
    460 470 480 490 500
    GVNIGLEVKS KTAKLQDFKS FLLKDSETSQ RLANLRQRVE QFARAFPMPG

    FDEH
    Length:504
    Mass (Da):55,993
    Last modified:May 30, 2000 - v3
    Checksum:i7A13AF741C68FFD6
    GO
    Isoform 2 (identifier: P34897-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         199-208: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:494
    Mass (Da):54,863
    Checksum:iA304DE25F96E942E
    GO
    Isoform 3 (identifier: P34897-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-21: Missing.

    Show »
    Length:483
    Mass (Da):53,455
    Checksum:i9F8925E18D758E65
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti308P → L in AAA63258 (PubMed:8505317).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0438441 – 21Missing in isoform 3. 1 PublicationAdd BLAST21
    Alternative sequenceiVSP_043088199 – 208Missing in isoform 2. 1 Publication10

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK315916 mRNA. Translation: BAH14287.1.
    BT006866 mRNA. Translation: AAP35512.1.
    AC137834 Genomic DNA. No translation available.
    CH471054 Genomic DNA. Translation: EAW96994.1.
    CH471054 Genomic DNA. Translation: EAW96998.1.
    BC011911 mRNA. Translation: AAH11911.1.
    BC013677 mRNA. Translation: AAH13677.1.
    BC032584 mRNA. Translation: AAH32584.1.
    BC044211 mRNA. Translation: AAH44211.1.
    Y12331 Genomic DNA. Translation: CAA72999.1.
    U23143 Genomic DNA. Translation: AAA64572.1.
    L11932 mRNA. Translation: AAA63258.1.
    CCDSiCCDS53805.1. [P34897-3]
    CCDS55837.1. [P34897-2]
    CCDS8934.1. [P34897-1]
    PIRiB46746.
    RefSeqiNP_001159828.1. NM_001166356.1. [P34897-2]
    NP_001159829.1. NM_001166357.1. [P34897-3]
    NP_001159830.1. NM_001166358.1. [P34897-3]
    NP_001159831.1. NM_001166359.1. [P34897-3]
    NP_005403.2. NM_005412.5. [P34897-1]
    UniGeneiHs.741179.

    Genome annotation databases

    EnsembliENST00000328923; ENSP00000333667; ENSG00000182199. [P34897-1]
    ENST00000414700; ENSP00000406881; ENSG00000182199. [P34897-3]
    ENST00000449049; ENSP00000413770; ENSG00000182199. [P34897-3]
    ENST00000553474; ENSP00000452419; ENSG00000182199. [P34897-3]
    ENST00000557487; ENSP00000452315; ENSG00000182199. [P34897-2]
    GeneIDi6472.
    KEGGihsa:6472.
    UCSCiuc001sni.3. human. [P34897-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK315916 mRNA. Translation: BAH14287.1.
    BT006866 mRNA. Translation: AAP35512.1.
    AC137834 Genomic DNA. No translation available.
    CH471054 Genomic DNA. Translation: EAW96994.1.
    CH471054 Genomic DNA. Translation: EAW96998.1.
    BC011911 mRNA. Translation: AAH11911.1.
    BC013677 mRNA. Translation: AAH13677.1.
    BC032584 mRNA. Translation: AAH32584.1.
    BC044211 mRNA. Translation: AAH44211.1.
    Y12331 Genomic DNA. Translation: CAA72999.1.
    U23143 Genomic DNA. Translation: AAA64572.1.
    L11932 mRNA. Translation: AAA63258.1.
    CCDSiCCDS53805.1. [P34897-3]
    CCDS55837.1. [P34897-2]
    CCDS8934.1. [P34897-1]
    PIRiB46746.
    RefSeqiNP_001159828.1. NM_001166356.1. [P34897-2]
    NP_001159829.1. NM_001166357.1. [P34897-3]
    NP_001159830.1. NM_001166358.1. [P34897-3]
    NP_001159831.1. NM_001166359.1. [P34897-3]
    NP_005403.2. NM_005412.5. [P34897-1]
    UniGeneiHs.741179.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3OU5X-ray2.04A17-504[»]
    4PVFX-ray2.60A/B22-504[»]
    ProteinModelPortaliP34897.
    SMRiP34897.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi112368. 432 interactors.
    IntActiP34897. 34 interactors.
    MINTiMINT-3013548.
    STRINGi9606.ENSP00000333667.

    Chemistry databases

    DrugBankiDB00145. Glycine.
    DB00116. Tetrahydrofolic acid.

    PTM databases

    iPTMnetiP34897.
    PhosphoSitePlusiP34897.
    SwissPalmiP34897.

    Polymorphism and mutation databases

    BioMutaiSHMT2.
    DMDMi6226865.

    Proteomic databases

    EPDiP34897.
    PaxDbiP34897.
    PeptideAtlasiP34897.
    PRIDEiP34897.

    Protocols and materials databases

    DNASUi6472.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000328923; ENSP00000333667; ENSG00000182199. [P34897-1]
    ENST00000414700; ENSP00000406881; ENSG00000182199. [P34897-3]
    ENST00000449049; ENSP00000413770; ENSG00000182199. [P34897-3]
    ENST00000553474; ENSP00000452419; ENSG00000182199. [P34897-3]
    ENST00000557487; ENSP00000452315; ENSG00000182199. [P34897-2]
    GeneIDi6472.
    KEGGihsa:6472.
    UCSCiuc001sni.3. human. [P34897-1]

    Organism-specific databases

    CTDi6472.
    DisGeNETi6472.
    GeneCardsiSHMT2.
    HGNCiHGNC:10852. SHMT2.
    HPAiHPA020543.
    HPA020549.
    MIMi138450. gene.
    neXtProtiNX_P34897.
    OpenTargetsiENSG00000182199.
    PharmGKBiPA35755.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2467. Eukaryota.
    COG0112. LUCA.
    GeneTreeiENSGT00390000002762.
    HOGENOMiHOG000239405.
    HOVERGENiHBG002807.
    InParanoidiP34897.
    KOiK00600.
    OMAiMAIRCQH.
    OrthoDBiEOG091G05AU.
    PhylomeDBiP34897.
    TreeFamiTF314667.

    Enzyme and pathway databases

    UniPathwayiUPA00193.
    BioCyciMetaCyc:HS00049-MONOMER.
    ZFISH:HS00049-MONOMER.
    ReactomeiR-HSA-196757. Metabolism of folate and pterines.

    Miscellaneous databases

    ChiTaRSiSHMT2. human.
    EvolutionaryTraceiP34897.
    GenomeRNAii6472.
    PROiP34897.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000182199.
    CleanExiHS_SHMT2.
    ExpressionAtlasiP34897. baseline and differential.
    GenevisibleiP34897. HS.

    Family and domain databases

    CDDicd00378. SHMT. 1 hit.
    Gene3Di3.40.640.10. 1 hit.
    3.90.1150.10. 1 hit.
    HAMAPiMF_00051. SHMT. 1 hit.
    InterProiIPR015424. PyrdxlP-dep_Trfase.
    IPR015421. PyrdxlP-dep_Trfase_major_sub1.
    IPR015422. PyrdxlP-dep_Trfase_major_sub2.
    IPR001085. Ser_HO-MeTrfase.
    IPR019798. Ser_HO-MeTrfase_PLP_BS.
    [Graphical view]
    PANTHERiPTHR11680. PTHR11680. 1 hit.
    PfamiPF00464. SHMT. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000412. SHMT. 1 hit.
    SUPFAMiSSF53383. SSF53383. 1 hit.
    PROSITEiPS00096. SHMT. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiGLYM_HUMAN
    AccessioniPrimary (citable) accession number: P34897
    Secondary accession number(s): B7Z9F1
    , E7EQ19, E7EU43, O00740, Q8N1A5
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1994
    Last sequence update: May 30, 2000
    Last modified: November 30, 2016
    This is version 177 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    In eukaryotes there are two forms of the enzymes: a cytosolic one and a mitochondrial one.

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 12
      Human chromosome 12: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    4. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    5. 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.