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Protein

Serine hydroxymethyltransferase, mitochondrial

Gene

SHMT2

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

Functioni

Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:29364879, PubMed:25619277). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). 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). Also required for mitochondrial translation by producing 5,10-methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29452640, PubMed:29364879). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondia, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985).6 Publications

Miscellaneous

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

Caution

Catalytic activityi

5,10-methylenetetrahydrofolate + glycine + H2O = tetrahydrofolate + L-serine.3 Publications

Cofactori

pyridoxal 5'-phosphate1 Publication1 Publication

Enzyme regulationi

Hydroxymethyltransferase is inhibited by succinylation at Lys-280.1 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
    • identical protein binding Source: Ensembl
    • 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

    Keywordsi

    Molecular functionTransferase
    Biological processOne-carbon metabolism
    LigandPyridoxal phosphate

    Enzyme and pathway databases

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

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine hydroxymethyltransferase, mitochondrial (EC:2.1.2.13 Publications)
    Short name:
    SHMT
    Alternative name(s):
    Glycine hydroxymethyltransferase
    Serine methylase
    Gene namesi
    Name:SHMT2Imported
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 12

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000182199.10
    HGNCiHGNC:10852 SHMT2
    MIMi138450 gene
    neXtProtiNX_P34897

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

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

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi98E → L: Abolishes serine hydroxymethyltransferase activity, leading to oxidative phosphorylation deficiency; when associated with F-106. 1 Publication1
    Mutagenesisi103K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi106Y → F: Abolishes serine hydroxymethyltransferase activity, leading to oxidative phosphorylation deficiency; when associated with L-98. 1 Publication1
    Mutagenesisi280K → Q: Abolishes pyridoxal phosphate-binding, leading to oxidative phosphorylation deficiency. 1 Publication1
    Mutagenesisi280K → R or E: Decreased succinylation level and hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi302K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi356K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi464K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi469K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1
    Mutagenesisi474K → R or E: Does not affect succinylation level or hydroxymethyltransferase activity. 1 Publication1

    Organism-specific databases

    DisGeNETi6472
    OpenTargetsiENSG00000182199
    PharmGKBiPA35755

    Chemistry databases

    DrugBankiDB00145 Glycine
    DB00114 Pyridoxal Phosphate
    DB00116 Tetrahydrofolic acid

    Polymorphism and mutation databases

    BioMutaiSHMT2
    DMDMi6226865

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 29MitochondrionBy similarityAdd 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)lysine1 Publication1
    Modified residuei280N6-succinyllysine1 Publication1
    Modified residuei297N6-acetyllysineCombined sources1
    Modified residuei356N6-acetyllysineCombined sources1
    Modified residuei464N6-acetyllysineCombined sources1
    Modified residuei469N6-acetyllysineCombined sources1
    Modified residuei470PhosphoserineCombined sources1
    Modified residuei474N6-acetyllysineCombined sources1

    Post-translational modificationi

    Succinylation at Lys-280 inhibits the hydroxymethyltransferase activity. Desuccinylation by SIRT5 restores the activity, leading to promote cell proliferation.1 Publication

    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 (PubMed:29180469, PubMed:25619277). Homodimer; in the absence of bound pyridoxal 5'-phosphate (PubMed:29180469, PubMed:25619277). Pyridoxal 5'-phosphate binding mediates an important conformation change that is required for tetramerization (PubMed:25619277). Interacts with ABRAXAS2; the interaction is direct. Identified in a complex with ABRAXAS2 and the other subunits of the BRISC complex, at least composed of the ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Identified in a complex with ABRAXAS2 and IFNAR1 (PubMed:24075985). Interacts with KIRREL3 (PubMed:25902260).4 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi112368440 interactors.
    IntActiP34897 45 interactors.
    MINTiP34897
    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
    Turni166 – 169Combined sources4
    Helixi172 – 174Combined sources3
    Helixi185 – 189Combined sources5
    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
    Turni301 – 303Combined sources3
    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[»]
    5V7IX-ray2.47A/B29-504[»]
    5X3VX-ray2.85A/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
    OMAiRPLQRCG
    OrthoDBiEOG091G05AU
    PhylomeDBiP34897
    TreeFamiTF314667

    Family and domain databases

    CDDicd00378 SHMT, 1 hit
    Gene3Di3.40.640.101 hit
    3.90.1150.102 hits
    HAMAPiMF_00051 SHMT, 1 hit
    InterProiView protein in InterPro
    IPR015424 PyrdxlP-dep_Trfase
    IPR015422 PyrdxlP-dep_Trfase_dom1
    IPR015421 PyrdxlP-dep_Trfase_major
    IPR001085 Ser_HO-MeTrfase
    IPR019798 Ser_HO-MeTrfase_PLP_BS
    PIRSFiPIRSF000412 SHMT, 1 hit
    SUPFAMiSSF53383 SSF53383, 1 hit
    PROSITEiView protein in PROSITE
    PS00096 SHMT, 1 hit

    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

    Similar proteinsi

    Entry informationi

    Entry nameiGLYM_HUMAN
    AccessioniPrimary (citable) accession number: P34897
    Secondary accession number(s): B7Z9F1
    , E7EQ19, E7EU43, O00740, Q8N1A5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
    Last sequence update: May 30, 2000
    Last modified: April 25, 2018
    This is version 193 of the entry and version 3 of the sequence. See 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

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome