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UniProtKB - P13995 (MTDC_HUMAN)
Protein
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Gene
MTHFD2
Organism
Homo sapiens (Human)
Status
Functioni
Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.
1 PublicationMiscellaneous
This NAD-dependent bifunctional enzyme has very different kinetic properties than the larger NADP-dependent trifunctional enzyme and is unique in that it requires formation of an enzyme-magnesium complex to allow binding of NAD.
Catalytic activityi
- (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NAD+ = 5,10-methenyltetrahydrofolate + NADH2 PublicationsEC:1.5.1.152 Publications
- EC:3.5.4.91 Publication
Cofactori
Mg2+1 Publication
Kineticsi
- KM=202 µM for NAD1 Publication
- KM=352 µM for NADP1 Publication
- Vmax=22.5 µmol/min/mg enzyme with NAD as substrate1 Publication
- Vmax=2.92 µmol/min/mg enzyme with NADP as substrate1 Publication
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 233 | NAD2 Publications | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 200 – 202 | NAD2 Publications | 3 |
GO - Molecular functioni
- magnesium ion binding Source: UniProtKB
- methenyltetrahydrofolate cyclohydrolase activity Source: UniProtKB
- methylenetetrahydrofolate dehydrogenase (NAD+) activity Source: UniProtKB
- methylenetetrahydrofolate dehydrogenase (NADP+) activity Source: UniProtKB
- phosphate ion binding Source: UniProtKB
GO - Biological processi
- folic acid metabolic process Source: Reactome
- tetrahydrofolate interconversion Source: GO_Central
- tetrahydrofolate metabolic process Source: UniProtKB
Keywordsi
Molecular function | Hydrolase, Multifunctional enzyme, Oxidoreductase |
Biological process | One-carbon metabolism |
Ligand | Magnesium, NAD, NADP |
Enzyme and pathway databases
BRENDAi | 1.5.1.15, 2681 1.5.1.5, 2681 3.5.4.9, 2681 |
PathwayCommonsi | P13995 |
Reactomei | R-HSA-196757, Metabolism of folate and pterines |
SABIO-RKi | P13995 |
SignaLinki | P13995 |
Names & Taxonomyi
Protein namesi | |
Gene namesi | Name:MTHFD2 Synonyms:NMDMC |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:7434, MTHFD2 |
MIMi | 604887, gene |
neXtProti | NX_P13995 |
VEuPathDBi | HostDB:ENSG00000065911 |
Subcellular locationi
Mitochondrion
Extracellular region or secreted
- extracellular space Source: UniProtKB
Mitochondrion
- mitochondrial matrix Source: Reactome
- mitochondrion Source: HPA
Keywords - Cellular componenti
MitochondrionPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 168 | D → A: Significant loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication | 1 | |
Mutagenesisi | 168 | D → E: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication | 1 | |
Mutagenesisi | 168 | D → N: 80% decrease in NAD-dependent dehydrogenase specific activity. 18% decrease in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication | 1 | |
Mutagenesisi | 168 | D → S: 82% decrease in NAD-dependent dehydrogenase specific activity. 65% decrease in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication | 1 | |
Mutagenesisi | 201 | R → A, S or K: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication | 1 | |
Mutagenesisi | 225 | D → A, S or E: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication | 1 | |
Mutagenesisi | 225 | D → N: 84% decrease in NAD-dependent dehydrogenase specific activity. 36% increase in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication | 1 | |
Mutagenesisi | 233 | R → A: Significant loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication | 1 | |
Mutagenesisi | 233 | R → K: 50% decrease in NAD and NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication | 1 | |
Mutagenesisi | 233 | R → S: Almost complete loss of NAD-dependent dehydrogenase specific activity. 50% decrease in NADP-dependent dehydrogenase specific activity. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 10797 |
OpenTargetsi | ENSG00000065911 |
PharmGKBi | PA31238 |
Miscellaneous databases
Pharosi | P13995, Tchem |
Chemistry databases
ChEMBLi | CHEMBL3621036 |
DrugBanki | DB00157, NADH DB00116, Tetrahydrofolic acid |
Genetic variation databases
BioMutai | MTHFD2 |
DMDMi | 115311607 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Transit peptidei | 1 – 35 | MitochondrionCombined sourcesAdd BLAST | 35 | |
ChainiPRO_0000034049 | 36 – 350 | Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrialAdd BLAST | 315 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 50 | N6-acetyllysine; alternateCombined sources | 1 | |
Cross-linki | 50 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources |
Keywords - PTMi
Acetylation, Isopeptide bond, Ubl conjugationProteomic databases
EPDi | P13995 |
jPOSTi | P13995 |
MassIVEi | P13995 |
MaxQBi | P13995 |
PaxDbi | P13995 |
PeptideAtlasi | P13995 |
PRIDEi | P13995 |
ProteomicsDBi | 53016 [P13995-1] 69375 |
PTM databases
GlyGeni | P13995, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P13995 |
PhosphoSitePlusi | P13995 |
Expressioni
Developmental stagei
Expressed only in developing normal tissues.
Gene expression databases
Bgeei | ENSG00000065911, Expressed in left coronary artery and 240 other tissues |
ExpressionAtlasi | P13995, baseline and differential |
Genevisiblei | P13995, HS |
Organism-specific databases
HPAi | ENSG00000065911, Low tissue specificity |
Interactioni
Subunit structurei
Homodimer.
1 PublicationBinary interactionsi
P13995
With | #Exp. | IntAct |
---|---|---|
NAGK - isoform 2 [Q9UJ70-2] | 3 | EBI-1058895,EBI-11526455 |
Protein-protein interaction databases
BioGRIDi | 116011, 81 interactors |
IntActi | P13995, 23 interactors |
MINTi | P13995 |
STRINGi | 9606.ENSP00000377617 |
Chemistry databases
BindingDBi | P13995 |
Miscellaneous databases
RNActi | P13995, protein |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details3D structure databases
SMRi | P13995 |
ModBasei | Search... |
PDBe-KBi | Search... |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 84 – 88 | Substrate binding1 Publication | 5 | |
Regioni | 131 – 133 | Substrate binding1 Publication | 3 | |
Regioni | 309 – 313 | Substrate binding1 Publication | 5 |
Sequence similaritiesi
Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.Curated
Keywords - Domaini
Transit peptidePhylogenomic databases
eggNOGi | KOG0089, Eukaryota |
GeneTreei | ENSGT00940000154863 |
HOGENOMi | CLU_034045_0_1_1 |
InParanoidi | P13995 |
OMAi | WSKKTCE |
OrthoDBi | 1004679at2759 |
PhylomeDBi | P13995 |
TreeFami | TF323998 |
Family and domain databases
CDDi | cd01080, NAD_bind_m-THF_DH_Cyclohyd, 1 hit |
HAMAPi | MF_01576, THF_DHG_CYH, 1 hit |
InterProi | View protein in InterPro IPR036291, NAD(P)-bd_dom_sf IPR000672, THF_DH/CycHdrlase IPR020630, THF_DH/CycHdrlase_cat_dom IPR020867, THF_DH/CycHdrlase_CS IPR020631, THF_DH/CycHdrlase_NAD-bd_dom |
Pfami | View protein in Pfam PF00763, THF_DHG_CYH, 1 hit PF02882, THF_DHG_CYH_C, 1 hit |
PRINTSi | PR00085, THFDHDRGNASE |
SUPFAMi | SSF51735, SSF51735, 1 hit |
PROSITEi | View protein in PROSITE PS00766, THF_DHG_CYH_1, 1 hit PS00767, THF_DHG_CYH_2, 1 hit |
s (2+)i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis entry has 2 described isoforms and 9 potential isoforms that are computationally mapped.Show allAlign All
Isoform 1 (identifier: P13995-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MAATSLMSAL AARLLQPAHS CSLRLRPFHL AAVRNEAVVI SGRKLAQQIK
60 70 80 90 100
QEVRQEVEEW VASGNKRPHL SVILVGENPA SHSYVLNKTR AAAVVGINSE
110 120 130 140 150
TIMKPASISE EELLNLINKL NNDDNVDGLL VQLPLPEHID ERRICNAVSP
160 170 180 190 200
DKDVDGFHVI NVGRMCLDQY SMLPATPWGV WEIIKRTGIP TLGKNVVVAG
210 220 230 240 250
RSKNVGMPIA MLLHTDGAHE RPGGDATVTI SHRYTPKEQL KKHTILADIV
260 270 280 290 300
ISAAGIPNLI TADMIKEGAA VIDVGINRVH DPVTAKPKLV GDVDFEGVRQ
310 320 330 340 350
KAGYITPVPG GVGPMTVAML MKNTIIAAKK VLRLEEREVL KSKELGVATN
Computationally mapped potential isoform sequencesi
There are 9 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketA0A7I2V2U6 | A0A7I2V2U6_HUMAN | Methenyltetrahydrofolate cyclohydro... | MTHFD2 | 324 | Annotation score: | ||
A0A7I2V482 | A0A7I2V482_HUMAN | Methenyltetrahydrofolate cyclohydro... | MTHFD2 | 212 | Annotation score: | ||
A0A7I2YQD4 | A0A7I2YQD4_HUMAN | Methenyltetrahydrofolate cyclohydro... | MTHFD2 | 203 | Annotation score: | ||
B9A062 | B9A062_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 222 | Annotation score: | ||
B8ZZU9 | B8ZZU9_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 267 | Annotation score: | ||
F8WF89 | F8WF89_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 37 | Annotation score: | ||
F8WF06 | F8WF06_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 38 | Annotation score: | ||
A0A7I2V3T1 | A0A7I2V3T1_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 36 | Annotation score: | ||
A0A7I2V2G4 | A0A7I2V2G4_HUMAN | Bifunctional methylenetetrahydrofol... | MTHFD2 | 36 | Annotation score: |
Sequence cautioni
The sequence AAX93061 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAD96546 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAD96761 differs from that shown. Reason: Erroneous initiation.Curated
The sequence CAA34431 differs from that shown. Reason: Erroneous initiation.Curated
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 75 | V → A in BAD96546 (Ref. 3) Curated | 1 | |
Sequence conflicti | 95 | V → A in BAD96761 (Ref. 3) Curated | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_056188 | 1 – 102 | Missing in isoform 2. 2 PublicationsAdd BLAST | 102 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X16396 mRNA Translation: CAA34431.1 Different initiation. AK300035 mRNA Translation: BAG61846.1 AK222826 mRNA Translation: BAD96546.1 Different initiation. AK223041 mRNA Translation: BAD96761.1 Different initiation. AC073263 Genomic DNA Translation: AAX93061.1 Different initiation. CH471053 Genomic DNA Translation: EAW99671.1 CH471053 Genomic DNA Translation: EAW99672.1 BC001548 mRNA Translation: AAH01548.2 BC015062 mRNA Translation: AAH15062.1 BC017054 mRNA Translation: AAH17054.2 |
CCDSi | CCDS1935.2 [P13995-1] |
PIRi | S14902, DEHUMT |
RefSeqi | NP_006627.2, NM_006636.3 [P13995-1] XP_006711987.1, XM_006711924.2 [P13995-2] |
Genome annotation databases
Ensembli | ENST00000394053; ENSP00000377617; ENSG00000065911 ENST00000677170; ENSP00000503486; ENSG00000065911 [P13995-2] ENST00000678623; ENSP00000504392; ENSG00000065911 [P13995-2] ENST00000678684; ENSP00000504687; ENSG00000065911 [P13995-2] ENST00000678731; ENSP00000503927; ENSG00000065911 [P13995-2] ENST00000679055; ENSP00000503701; ENSG00000065911 [P13995-2] |
GeneIDi | 10797 |
KEGGi | hsa:10797 |
MANE-Selecti | ENST00000394053.7; ENSP00000377617.2; NM_006636.4; NP_006627.2 |
UCSCi | uc002skk.4, human [P13995-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X16396 mRNA Translation: CAA34431.1 Different initiation. AK300035 mRNA Translation: BAG61846.1 AK222826 mRNA Translation: BAD96546.1 Different initiation. AK223041 mRNA Translation: BAD96761.1 Different initiation. AC073263 Genomic DNA Translation: AAX93061.1 Different initiation. CH471053 Genomic DNA Translation: EAW99671.1 CH471053 Genomic DNA Translation: EAW99672.1 BC001548 mRNA Translation: AAH01548.2 BC015062 mRNA Translation: AAH15062.1 BC017054 mRNA Translation: AAH17054.2 |
CCDSi | CCDS1935.2 [P13995-1] |
PIRi | S14902, DEHUMT |
RefSeqi | NP_006627.2, NM_006636.3 [P13995-1] XP_006711987.1, XM_006711924.2 [P13995-2] |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
5TC4 | X-ray | 1.89 | A | 36-350 | [»] | |
6JIB | X-ray | 2.25 | A/B | 36-338 | [»] | |
6JID | X-ray | 2.50 | A/B | 36-338 | [»] | |
6KG2 | X-ray | 2.25 | A/B | 36-338 | [»] | |
6S4A | X-ray | 1.95 | A/B | 36-350 | [»] | |
6S4E | X-ray | 1.90 | A | 36-350 | [»] | |
6S4F | X-ray | 2.20 | A/B | 36-350 | [»] | |
7EHJ | X-ray | 2.16 | A/B | 36-350 | [»] | |
7EHM | X-ray | 2.13 | A/B | 36-350 | [»] | |
7EHN | X-ray | 2.25 | A/B | 36-350 | [»] | |
7EHV | X-ray | 2.61 | A/B | 36-350 | [»] | |
SMRi | P13995 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 116011, 81 interactors |
IntActi | P13995, 23 interactors |
MINTi | P13995 |
STRINGi | 9606.ENSP00000377617 |
Chemistry databases
BindingDBi | P13995 |
ChEMBLi | CHEMBL3621036 |
DrugBanki | DB00157, NADH DB00116, Tetrahydrofolic acid |
PTM databases
GlyGeni | P13995, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P13995 |
PhosphoSitePlusi | P13995 |
Genetic variation databases
BioMutai | MTHFD2 |
DMDMi | 115311607 |
Proteomic databases
EPDi | P13995 |
jPOSTi | P13995 |
MassIVEi | P13995 |
MaxQBi | P13995 |
PaxDbi | P13995 |
PeptideAtlasi | P13995 |
PRIDEi | P13995 |
ProteomicsDBi | 53016 [P13995-1] 69375 |
Protocols and materials databases
Antibodypediai | 3292, 194 antibodies from 30 providers |
DNASUi | 10797 |
Genome annotation databases
Ensembli | ENST00000394053; ENSP00000377617; ENSG00000065911 ENST00000677170; ENSP00000503486; ENSG00000065911 [P13995-2] ENST00000678623; ENSP00000504392; ENSG00000065911 [P13995-2] ENST00000678684; ENSP00000504687; ENSG00000065911 [P13995-2] ENST00000678731; ENSP00000503927; ENSG00000065911 [P13995-2] ENST00000679055; ENSP00000503701; ENSG00000065911 [P13995-2] |
GeneIDi | 10797 |
KEGGi | hsa:10797 |
MANE-Selecti | ENST00000394053.7; ENSP00000377617.2; NM_006636.4; NP_006627.2 |
UCSCi | uc002skk.4, human [P13995-1] |
Organism-specific databases
CTDi | 10797 |
DisGeNETi | 10797 |
GeneCardsi | MTHFD2 |
HGNCi | HGNC:7434, MTHFD2 |
HPAi | ENSG00000065911, Low tissue specificity |
MIMi | 604887, gene |
neXtProti | NX_P13995 |
OpenTargetsi | ENSG00000065911 |
PharmGKBi | PA31238 |
VEuPathDBi | HostDB:ENSG00000065911 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0089, Eukaryota |
GeneTreei | ENSGT00940000154863 |
HOGENOMi | CLU_034045_0_1_1 |
InParanoidi | P13995 |
OMAi | WSKKTCE |
OrthoDBi | 1004679at2759 |
PhylomeDBi | P13995 |
TreeFami | TF323998 |
Enzyme and pathway databases
BRENDAi | 1.5.1.15, 2681 1.5.1.5, 2681 3.5.4.9, 2681 |
PathwayCommonsi | P13995 |
Reactomei | R-HSA-196757, Metabolism of folate and pterines |
SABIO-RKi | P13995 |
SignaLinki | P13995 |
Miscellaneous databases
BioGRID-ORCSi | 10797, 44 hits in 1057 CRISPR screens |
GeneWikii | MTHFD2 |
GenomeRNAii | 10797 |
Pharosi | P13995, Tchem |
PROi | PR:P13995 |
RNActi | P13995, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000065911, Expressed in left coronary artery and 240 other tissues |
ExpressionAtlasi | P13995, baseline and differential |
Genevisiblei | P13995, HS |
Family and domain databases
CDDi | cd01080, NAD_bind_m-THF_DH_Cyclohyd, 1 hit |
HAMAPi | MF_01576, THF_DHG_CYH, 1 hit |
InterProi | View protein in InterPro IPR036291, NAD(P)-bd_dom_sf IPR000672, THF_DH/CycHdrlase IPR020630, THF_DH/CycHdrlase_cat_dom IPR020867, THF_DH/CycHdrlase_CS IPR020631, THF_DH/CycHdrlase_NAD-bd_dom |
Pfami | View protein in Pfam PF00763, THF_DHG_CYH, 1 hit PF02882, THF_DHG_CYH_C, 1 hit |
PRINTSi | PR00085, THFDHDRGNASE |
SUPFAMi | SSF51735, SSF51735, 1 hit |
PROSITEi | View protein in PROSITE PS00766, THF_DHG_CYH_1, 1 hit PS00767, THF_DHG_CYH_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | MTDC_HUMAN | |
Accessioni | P13995Primary (citable) accession number: P13995 Secondary accession number(s): Q53G90 Q7Z650 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | January 1, 1990 |
Last sequence update: | September 19, 2006 | |
Last modified: | February 23, 2022 | |
This is version 217 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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, Reference proteomeDocuments
- Human chromosome 2
Human chromosome 2: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families