MTHFS_HUMAN
ID MTHFS_HUMAN Reviewed; 203 AA.
AC P49914; H3BQ75;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=5-formyltetrahydrofolate cyclo-ligase;
DE EC=6.3.3.2;
DE AltName: Full=5,10-methenyl-tetrahydrofolate synthetase;
DE Short=MTHFS;
DE Short=Methenyl-THF synthetase;
GN Name=MTHFS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Liver;
RX PubMed=8522195; DOI=10.1016/0378-1119(95)00321-v;
RA Dayan A., Bertrand R., Beauchemin M., Chahla D., Mamo A., Filion M.,
RA Skup D., Massie B., Jolivet J.;
RT "Cloning and characterization of the human 5,10-methenyltetrahydrofolate
RT synthetase-encoding cDNA.";
RL Gene 165:307-311(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain cortex, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP CHARACTERIZATION.
RX PubMed=3801490; DOI=10.1016/0167-4838(87)90004-5;
RA Bertrand R., MacKenzie R.E., Jolivet J.;
RT "Human liver methenyltetrahydrofolate synthetase: improved purification and
RT increased affinity for folate polyglutamate substrates.";
RL Biochim. Biophys. Acta 911:154-161(1987).
RN [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [7]
RP INVOLVEMENT IN NEDMEHM, AND VARIANTS NEDMEHM PRO-36; GLN-145 AND
RP 162-GLN--ALA-203 DEL.
RX PubMed=30031689; DOI=10.1016/j.ymgme.2018.06.006;
RG Undiagnosed Diseases Network (UDN);
RA Rodan L.H., Qi W., Ducker G.S., Demirbas D., Laine R., Yang E.,
RA Walker M.A., Eichler F., Rabinowitz J.D., Anselm I., Berry G.T.;
RT "5,10-methenyltetrahydrofolate synthetase deficiency causes a
RT neurometabolic disorder associated with microcephaly, epilepsy, and
RT cerebral hypomyelination.";
RL Mol. Genet. Metab. 125:118-126(2018).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE; PRODUCT;
RP ADP AND MAGNESIUM IONS, AND MUTAGENESIS OF LYS-10; ARG-14; ARG-145; TYR-153
RP AND ASP-154.
RX PubMed=19738041; DOI=10.1158/0008-5472.can-09-1927;
RA Wu D., Li Y., Song G., Cheng C., Zhang R., Joachimiak A., Shaw N.,
RA Liu Z.-J.;
RT "Structural basis for the inhibition of human 5,10-methenyltetrahydrofolate
RT synthetase by N10-substituted folate analogues.";
RL Cancer Res. 69:7294-7301(2009).
CC -!- FUNCTION: Contributes to tetrahydrofolate metabolism. Helps regulate
CC carbon flow through the folate-dependent one-carbon metabolic network
CC that supplies carbon for the biosynthesis of purines, thymidine and
CC amino acids. Catalyzes the irreversible conversion of 5-
CC formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate.
CC {ECO:0000269|PubMed:8522195}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-formyl-5,6,7,8-tetrahydrofolate + ATP = 5,10-
CC methenyltetrahydrofolate + ADP + phosphate; Xref=Rhea:RHEA:10488,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57455,
CC ChEBI:CHEBI:57457, ChEBI:CHEBI:456216; EC=6.3.3.2;
CC Evidence={ECO:0000269|PubMed:8522195};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P49914-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P49914-2; Sequence=VSP_046863;
CC -!- DISEASE: Neurodevelopmental disorder with microcephaly, epilepsy, and
CC hypomyelination (NEDMEHM) [MIM:618367]: An autosomal recessive
CC neurodevelopmental disorder with onset at birth or in early infancy,
CC and characterized by microcephaly, short stature, severe global
CC developmental delay, progressive spasticity, and epilepsy. Brain
CC imaging shows delayed myelination, hypomyelination, enlarged
CC ventricles, and cerebellar atrophy. {ECO:0000269|PubMed:30031689}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the 5-formyltetrahydrofolate cyclo-ligase
CC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CK002935; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; L38928; AAC41945.1; -; mRNA.
DR EMBL; AC015871; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC021483; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC019921; AAH19921.1; -; mRNA.
DR EMBL; CK002935; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS10311.1; -. [P49914-1]
DR PIR; JC4389; JC4389.
DR RefSeq; NP_001186687.1; NM_001199758.1.
DR RefSeq; NP_006432.1; NM_006441.3. [P49914-1]
DR PDB; 3HXT; X-ray; 1.90 A; A=1-203.
DR PDB; 3HY3; X-ray; 1.80 A; A=1-203.
DR PDB; 3HY4; X-ray; 2.80 A; A=1-203.
DR PDB; 3HY6; X-ray; 2.10 A; A=1-203.
DR PDBsum; 3HXT; -.
DR PDBsum; 3HY3; -.
DR PDBsum; 3HY4; -.
DR PDBsum; 3HY6; -.
DR AlphaFoldDB; P49914; -.
DR BMRB; P49914; -.
DR SMR; P49914; -.
DR BioGRID; 115837; 9.
DR IntAct; P49914; 4.
DR STRING; 9606.ENSP00000258874; -.
DR iPTMnet; P49914; -.
DR PhosphoSitePlus; P49914; -.
DR SwissPalm; P49914; -.
DR BioMuta; MTHFS; -.
DR EPD; P49914; -.
DR jPOST; P49914; -.
DR MassIVE; P49914; -.
DR MaxQB; P49914; -.
DR PaxDb; P49914; -.
DR PeptideAtlas; P49914; -.
DR PRIDE; P49914; -.
DR ProteomicsDB; 41708; -.
DR ProteomicsDB; 56179; -. [P49914-1]
DR Antibodypedia; 1955; 230 antibodies from 28 providers.
DR DNASU; 10588; -.
DR Ensembl; ENST00000258874.4; ENSP00000258874.4; ENSG00000136371.11. [P49914-1]
DR GeneID; 10588; -.
DR KEGG; hsa:10588; -.
DR MANE-Select; ENST00000258874.4; ENSP00000258874.4; NM_006441.4; NP_006432.1.
DR UCSC; uc002bex.5; human. [P49914-1]
DR CTD; 10588; -.
DR DisGeNET; 10588; -.
DR GeneCards; MTHFS; -.
DR HGNC; HGNC:7437; MTHFS.
DR HPA; ENSG00000136371; Tissue enriched (liver).
DR MalaCards; MTHFS; -.
DR MIM; 604197; gene.
DR MIM; 618367; phenotype.
DR neXtProt; NX_P49914; -.
DR OpenTargets; ENSG00000136371; -.
DR OpenTargets; ENSG00000259332; -.
DR Orphanet; 597874; MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome.
DR PharmGKB; PA31239; -.
DR VEuPathDB; HostDB:ENSG00000136371; -.
DR eggNOG; KOG3093; Eukaryota.
DR GeneTree; ENSGT00390000017791; -.
DR HOGENOM; CLU_066245_2_1_1; -.
DR InParanoid; P49914; -.
DR OMA; MPLVGFD; -.
DR OrthoDB; 1425233at2759; -.
DR PhylomeDB; P49914; -.
DR TreeFam; TF313668; -.
DR BRENDA; 6.3.3.2; 2681.
DR PathwayCommons; P49914; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SignaLink; P49914; -.
DR BioGRID-ORCS; 10588; 8 hits in 1064 CRISPR screens.
DR EvolutionaryTrace; P49914; -.
DR GenomeRNAi; 10588; -.
DR Pharos; P49914; Tbio.
DR PRO; PR:P49914; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P49914; protein.
DR Bgee; ENSG00000136371; Expressed in right lobe of liver and 101 other tissues.
DR ExpressionAtlas; P49914; baseline and differential.
DR Genevisible; P49914; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:BHF-UCL.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0030272; F:5-formyltetrahydrofolate cyclo-ligase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:BHF-UCL.
DR GO; GO:0005542; F:folic acid binding; IDA:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046657; P:folic acid catabolic process; IMP:BHF-UCL.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0009396; P:folic acid-containing compound biosynthetic process; IBA:GO_Central.
DR GO; GO:0015942; P:formate metabolic process; NAS:UniProtKB.
DR GO; GO:0006536; P:glutamate metabolic process; IMP:BHF-UCL.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IMP:BHF-UCL.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; IDA:UniProtKB.
DR Gene3D; 3.40.50.10420; -; 1.
DR InterPro; IPR002698; FTHF_cligase.
DR InterPro; IPR024185; FTHF_cligase-like_sf.
DR InterPro; IPR037171; NagB/RpiA_transferase-like.
DR PANTHER; PTHR23407:SF1; PTHR23407:SF1; 1.
DR Pfam; PF01812; 5-FTHF_cyc-lig; 1.
DR PIRSF; PIRSF006806; FTHF_cligase; 1.
DR SUPFAM; SSF100950; SSF100950; 1.
DR TIGRFAMs; TIGR02727; MTHFS_bact; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Cytoplasm;
KW Disease variant; Epilepsy; Folate-binding; Ligase; Magnesium;
KW Metal-binding; Nucleotide-binding; Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..203
FT /note="5-formyltetrahydrofolate cyclo-ligase"
FT /id="PRO_0000200275"
FT BINDING 10..14
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 14
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 56
FT /ligand="substrate"
FT BINDING 61
FT /ligand="substrate"
FT BINDING 145..153
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 148..152
FT /ligand="substrate"
FT BINDING 154
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT BINDING 189
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT VAR_SEQ 1..39
FT /note="MAAAAVSSAKRSLRGELKQRLRAMSAEERLRQSRVLSQK -> MARSRLTAT
FT SVSQVQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_046863"
FT VARIANT 36
FT /note="L -> P (in NEDMEHM; dbSNP:rs1349638340)"
FT /evidence="ECO:0000269|PubMed:30031689"
FT /id="VAR_082088"
FT VARIANT 145
FT /note="R -> Q (in NEDMEHM; dbSNP:rs753635972)"
FT /evidence="ECO:0000269|PubMed:30031689"
FT /id="VAR_082089"
FT VARIANT 162..203
FT /note="Missing (in NEDMEHM)"
FT /evidence="ECO:0000269|PubMed:30031689"
FT /id="VAR_082090"
FT VARIANT 202
FT /note="T -> A (in dbSNP:rs8923)"
FT /id="VAR_034115"
FT MUTAGEN 10
FT /note="K->A: Reduces activity by 93%."
FT /evidence="ECO:0000269|PubMed:19738041"
FT MUTAGEN 14
FT /note="R->A: Reduces activity by 87%."
FT /evidence="ECO:0000269|PubMed:19738041"
FT MUTAGEN 61
FT /note="E->A: Reduces activity by 94%."
FT MUTAGEN 145
FT /note="R->A: Reduces activity by 98%."
FT /evidence="ECO:0000269|PubMed:19738041"
FT MUTAGEN 153
FT /note="Y->A: Reduces activity by 97%."
FT /evidence="ECO:0000269|PubMed:19738041"
FT MUTAGEN 154
FT /note="D->A: Reduces activity by 99%."
FT /evidence="ECO:0000269|PubMed:19738041"
FT CONFLICT 177
FT /note="E -> D (in Ref. 3; CK002935)"
FT /evidence="ECO:0000305"
FT CONFLICT 203
FT /note="A -> T (in Ref. 3; CK002935)"
FT /evidence="ECO:0000305"
FT HELIX 2..22
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 26..41
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 44..48
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 50..53
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 65..73
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 77..84
FT /evidence="ECO:0007829|PDB:3HY3"
FT TURN 85..88
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 89..95
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 98..101
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 123..125
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 130..134
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 137..139
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 152..160
FT /evidence="ECO:0007829|PDB:3HY3"
FT TURN 161..163
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 169..173
FT /evidence="ECO:0007829|PDB:3HY3"
FT HELIX 176..178
FT /evidence="ECO:0007829|PDB:3HY3"
FT STRAND 179..181
FT /evidence="ECO:0007829|PDB:3HXT"
FT STRAND 193..196
FT /evidence="ECO:0007829|PDB:3HY3"
SQ SEQUENCE 203 AA; 23256 MW; 658C4AE8FC7AB3F2 CRC64;
MAAAAVSSAK RSLRGELKQR LRAMSAEERL RQSRVLSQKV IAHSEYQKSK RISIFLSMQD
EIETEEIIKD IFQRGKICFI PRYRFQSNHM DMVRIESPEE ISLLPKTSWN IPQPGEGDVR
EEALSTGGLD LIFMPGLGFD KHGNRLGRGK GYYDAYLKRC LQHQEVKPYT LALAFKEQIC
LQVPVNENDM KVDEVLYEDS STA
