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Protein

5-formyltetrahydrofolate cyclo-ligase

Gene

MTHFS

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

Functioni

Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate.1 Publication

Catalytic activityi

ATP + 5-formyltetrahydrofolate = ADP + phosphate + 5,10-methenyltetrahydrofolate.1 Publication

Cofactori

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei14 – 141ATP
Binding sitei56 – 561Substrate; via carbonyl oxygen
Binding sitei61 – 611Substrate
Metal bindingi154 – 1541MagnesiumBy similarity
Metal bindingi189 – 1891MagnesiumBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi10 – 145ATP
Nucleotide bindingi145 – 1539ATP

GO - Molecular functioni

  1. 5-formyltetrahydrofolate cyclo-ligase activity Source: UniProtKB
  2. ATP binding Source: UniProtKB-KW
  3. folic acid binding Source: UniProtKB-KW
  4. metal ion binding Source: UniProtKB-KW

GO - Biological processi

  1. formate metabolic process Source: UniProtKB
  2. tetrahydrofolate metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Ligandi

ATP-binding, Folate-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi6.3.3.2. 2681.

Names & Taxonomyi

Protein namesi
Recommended name:
5-formyltetrahydrofolate cyclo-ligase (EC:6.3.3.2)
Alternative name(s):
5,10-methenyl-tetrahydrofolate synthetase
Short name:
MTHFS
Short name:
Methenyl-THF synthetase
Gene namesi
Name:MTHFS
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:7437. MTHFS.

Subcellular locationi

GO - Cellular componenti

  1. cytoplasm Source: HPA
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi10 – 101K → A: Reduces activity by 93%. 1 Publication
Mutagenesisi14 – 141R → A: Reduces activity by 87%. 1 Publication
Mutagenesisi61 – 611E → A: Reduces activity by 94%.
Mutagenesisi145 – 1451R → A: Reduces activity by 98%. 1 Publication
Mutagenesisi153 – 1531Y → A: Reduces activity by 97%. 1 Publication
Mutagenesisi154 – 1541D → A: Reduces activity by 99%. 1 Publication

Organism-specific databases

PharmGKBiPA31239.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed2 Publications
Chaini2 – 2032025-formyltetrahydrofolate cyclo-ligasePRO_0000200275Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine2 Publications

Keywords - PTMi

Acetylation

Proteomic databases

MaxQBiP49914.
PaxDbiP49914.
PRIDEiP49914.

PTM databases

PhosphoSiteiP49914.

Expressioni

Gene expression databases

BgeeiP49914.
CleanExiHS_MTHFS.
ExpressionAtlasiP49914. baseline.
GenevestigatoriP49914.

Organism-specific databases

HPAiHPA008067.
HPA054177.

Interactioni

Subunit structurei

Monomer.

Protein-protein interaction databases

BioGridi115837. 2 interactions.
IntActiP49914. 1 interaction.
STRINGi9606.ENSP00000258874.

Structurei

Secondary structure

1
203
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi2 – 2221Combined sources
Helixi26 – 4116Combined sources
Helixi44 – 485Combined sources
Beta strandi50 – 534Combined sources
Helixi65 – 739Combined sources
Beta strandi77 – 848Combined sources
Turni85 – 884Combined sources
Beta strandi89 – 957Combined sources
Helixi98 – 1014Combined sources
Helixi123 – 1253Combined sources
Beta strandi130 – 1345Combined sources
Beta strandi137 – 1393Combined sources
Beta strandi148 – 1503Combined sources
Helixi152 – 1609Combined sources
Turni161 – 1633Combined sources
Beta strandi169 – 1735Combined sources
Helixi176 – 1783Combined sources
Beta strandi179 – 1813Combined sources
Beta strandi193 – 1964Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3HXTX-ray1.90A1-203[»]
3HY3X-ray1.80A1-203[»]
3HY4X-ray2.80A1-203[»]
3HY6X-ray2.10A1-203[»]
ProteinModelPortaliP49914.
SMRiP49914. Positions 1-198.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49914.

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni148 – 1525Substrate binding

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0212.
GeneTreeiENSGT00390000017791.
HOGENOMiHOG000007299.
HOVERGENiHBG052525.
InParanoidiP49914.
KOiK01934.
OMAiHSEYQKS.
OrthoDBiEOG73806H.
PhylomeDBiP49914.
TreeFamiTF313668.

Family and domain databases

Gene3Di3.40.50.10420. 1 hit.
InterProiIPR002698. FTHF_cligase.
IPR024185. FTHF_cligase-like.
[Graphical view]
PANTHERiPTHR23407:SF1. PTHR23407:SF1. 1 hit.
PfamiPF01812. 5-FTHF_cyc-lig. 1 hit.
[Graphical view]
PIRSFiPIRSF006806. FTHF_cligase. 1 hit.
TIGRFAMsiTIGR02727. MTHFS_bact. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P49914-1) [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
MAAAAVSSAK RSLRGELKQR LRAMSAEERL RQSRVLSQKV IAHSEYQKSK
60 70 80 90 100
RISIFLSMQD EIETEEIIKD IFQRGKICFI PRYRFQSNHM DMVRIESPEE
110 120 130 140 150
ISLLPKTSWN IPQPGEGDVR EEALSTGGLD LIFMPGLGFD KHGNRLGRGK
160 170 180 190 200
GYYDAYLKRC LQHQEVKPYT LALAFKEQIC LQVPVNENDM KVDEVLYEDS

STA
Length:203
Mass (Da):23,256
Last modified:January 23, 2007 - v2
Checksum:i658C4AE8FC7AB3F2
GO
Isoform 2 (identifier: P49914-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-39: MAAAAVSSAKRSLRGELKQRLRAMSAEERLRQSRVLSQK → MARSRLTATSVSQVQ

Note: No experimental confirmation available.

Show »
Length:179
Mass (Da):20,519
Checksum:iDE1ACF55C16F8B49
GO

Sequence cautioni

The sequence CK002935 differs from that shown. Reason: Frameshift at positions 178 and 201. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti177 – 1771E → D in CK002935 (PubMed:15489334).Curated
Sequence conflicti203 – 2031A → T in CK002935 (PubMed:15489334).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti202 – 2021T → A.
Corresponds to variant rs8923 [ dbSNP | Ensembl ].
VAR_034115

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 3939MAAAA…VLSQK → MARSRLTATSVSQVQ in isoform 2. 1 PublicationVSP_046863Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L38928 mRNA. Translation: AAC41945.1.
AC015871 Genomic DNA. No translation available.
AC021483 Genomic DNA. No translation available.
BC019921 mRNA. Translation: AAH19921.1.
CK002935 mRNA. No translation available.
CCDSiCCDS10311.1. [P49914-1]
PIRiJC4389.
RefSeqiNP_001186687.1. NM_001199758.1.
NP_006432.1. NM_006441.3. [P49914-1]
UniGeneiHs.194294.
Hs.459049.

Genome annotation databases

EnsembliENST00000258874; ENSP00000258874; ENSG00000136371. [P49914-1]
GeneIDi10588.
KEGGihsa:100528021.
hsa:10588.
UCSCiuc002bex.4. human. [P49914-1]
uc021srr.1. human.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L38928 mRNA. Translation: AAC41945.1.
AC015871 Genomic DNA. No translation available.
AC021483 Genomic DNA. No translation available.
BC019921 mRNA. Translation: AAH19921.1.
CK002935 mRNA. No translation available.
CCDSiCCDS10311.1. [P49914-1]
PIRiJC4389.
RefSeqiNP_001186687.1. NM_001199758.1.
NP_006432.1. NM_006441.3. [P49914-1]
UniGeneiHs.194294.
Hs.459049.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3HXTX-ray1.90A1-203[»]
3HY3X-ray1.80A1-203[»]
3HY4X-ray2.80A1-203[»]
3HY6X-ray2.10A1-203[»]
ProteinModelPortaliP49914.
SMRiP49914. Positions 1-198.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115837. 2 interactions.
IntActiP49914. 1 interaction.
STRINGi9606.ENSP00000258874.

PTM databases

PhosphoSiteiP49914.

Proteomic databases

MaxQBiP49914.
PaxDbiP49914.
PRIDEiP49914.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000258874; ENSP00000258874; ENSG00000136371. [P49914-1]
GeneIDi10588.
KEGGihsa:100528021.
hsa:10588.
UCSCiuc002bex.4. human. [P49914-1]
uc021srr.1. human.

Organism-specific databases

CTDi100528021.
10588.
GeneCardsiGC15M080125.
HGNCiHGNC:7437. MTHFS.
HPAiHPA008067.
HPA054177.
MIMi604197. gene.
neXtProtiNX_P49914.
PharmGKBiPA31239.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0212.
GeneTreeiENSGT00390000017791.
HOGENOMiHOG000007299.
HOVERGENiHBG052525.
InParanoidiP49914.
KOiK01934.
OMAiHSEYQKS.
OrthoDBiEOG73806H.
PhylomeDBiP49914.
TreeFamiTF313668.

Enzyme and pathway databases

BRENDAi6.3.3.2. 2681.

Miscellaneous databases

ChiTaRSiMTHFS. human.
EvolutionaryTraceiP49914.
NextBioi34054968.
PROiP49914.
SOURCEiSearch...

Gene expression databases

BgeeiP49914.
CleanExiHS_MTHFS.
ExpressionAtlasiP49914. baseline.
GenevestigatoriP49914.

Family and domain databases

Gene3Di3.40.50.10420. 1 hit.
InterProiIPR002698. FTHF_cligase.
IPR024185. FTHF_cligase-like.
[Graphical view]
PANTHERiPTHR23407:SF1. PTHR23407:SF1. 1 hit.
PfamiPF01812. 5-FTHF_cyc-lig. 1 hit.
[Graphical view]
PIRSFiPIRSF006806. FTHF_cligase. 1 hit.
TIGRFAMsiTIGR02727. MTHFS_bact. 1 hit.
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning and characterization of the human 5,10-methenyltetrahydrofolate synthetase-encoding cDNA."
    Dayan A., Bertrand R., Beauchemin M., Chahla D., Mamo A., Filion M., Skup D., Massie B., Jolivet J.
    Gene 165:307-311(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY.
    Tissue: Liver.
  2. "Analysis of the DNA sequence and duplication history of human chromosome 15."
    Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., Abouelleil A.
    , Arachchi H.M., Baradarani L., Birditt B., Bloom S., Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.
    Nature 440:671-675(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    Tissue: Brain cortex and Pancreas.
  4. "Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates."
    Bertrand R., MacKenzie R.E., Jolivet J.
    Biochim. Biophys. Acta 911:154-161(1986) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION.
  5. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
    Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
    Anal. Chem. 81:4493-4501(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
  6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  7. Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
  8. "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
    Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., Ye M., Zou H.
    J. Proteomics 96:253-262(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  9. "Structural basis for the inhibition of human 5,10-methenyltetrahydrofolate synthetase by N10-substituted folate analogues."
    Wu D., Li Y., Song G., Cheng C., Zhang R., Joachimiak A., Shaw N., Liu Z.-J.
    Cancer Res. 69:7294-7301(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE; PRODUCT; ADP AND MAGNESIUM IONS, MUTAGENESIS OF LYS-10; ARG-14; ARG-145; TYR-153 AND ASP-154.

Entry informationi

Entry nameiMTHFS_HUMAN
AccessioniPrimary (citable) accession number: P49914
Secondary accession number(s): H3BQ75
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: January 23, 2007
Last modified: April 1, 2015
This is version 132 of the entry and version 2 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.