MTHFD2 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase [Homo sapiens (human)] - Gene

Summary

Official Symbol: MTHFD2provided by HGNC
Official Full Name: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolaseprovided by HGNC
Primary source: HGNC:HGNC:7434
See related: Ensembl:ENSG00000065911 MIM:604887; AllianceGenome:HGNC:7434
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: NMDMC
Summary: This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The enzyme functions as a homodimer and is unique in its absolute requirement for magnesium and inorganic phosphate. Formation of the enzyme-magnesium complex allows binding of NAD. Alternative splicing results in two different transcripts, one protein-coding and the other not protein-coding. This gene has a pseudogene on chromosome 7. [provided by RefSeq, Mar 2009]
Expression: Ubiquitous expression in appendix (RPKM 27.6), lymph node (RPKM 27.0) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2p13.1

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (74198615..74217565)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (74207390..74226316)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (74425742..74444692)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.
Title: Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.
Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.
Title: Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.
SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression.
Title: SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression.
MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.
Title: MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.
Upregulation of MTHFD2 is associated with PDL1 activation in bladder cancer via the PI3K/AKT pathway.
Title: Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway.
Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
Title: Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
Title: Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
ATF4/MYC Regulates MTHFD2 to Promote NSCLC Progression by Mediating Redox Homeostasis.
Title: ATF4/MYC Regulates MTHFD2 to Promote NSCLC Progression by Mediating Redox Homeostasis.
Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
Title: Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
[Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring].", trans "MTHFD1MTHFD2.
Title: [Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring].

Submit: New GeneRIF Correction See all GeneRIFs (41)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Nef	nef	HIV-1 Nef is identified to have a physical interaction with methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses	PubMed

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Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH47176 (e-PCR)
- UniSTS:90153

SHGC-168 (e-PCR)
- UniSTS:89642

G07090 (e-PCR)
- UniSTS:11379

D14S71 (e-PCR), detects polymorphism
- UniSTS:71293

RH70261 (e-PCR)
- UniSTS:86968

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables magnesium ion binding	IDA Inferred from Direct Assay more info	PubMed
enables magnesium ion binding	IMP Inferred from Mutant Phenotype more info	PubMed
enables methenyltetrahydrofolate cyclohydrolase activity	IBA Inferred from Biological aspect of Ancestor more info
enables methenyltetrahydrofolate cyclohydrolase activity	IDA Inferred from Direct Assay more info	PubMed
enables methenyltetrahydrofolate cyclohydrolase activity	ISS Inferred from Sequence or Structural Similarity more info	PubMed
enables methenyltetrahydrofolate cyclohydrolase activity	TAS Traceable Author Statement more info
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity	IBA Inferred from Biological aspect of Ancestor more info
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity	IDA Inferred from Direct Assay more info	PubMed
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity	TAS Traceable Author Statement more info
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	IBA Inferred from Biological aspect of Ancestor more info
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	IDA Inferred from Direct Assay more info	PubMed
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables phosphate ion binding	IDA Inferred from Direct Assay more info	PubMed
enables phosphate ion binding	IMP Inferred from Mutant Phenotype more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
involved_in folic acid metabolic process	TAS Traceable Author Statement more info
involved_in tetrahydrofolate interconversion	IBA Inferred from Biological aspect of Ancestor more info
involved_in tetrahydrofolate metabolic process	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
located_in extracellular space	HDA more info	PubMed
located_in mitochondrial matrix	TAS Traceable Author Statement more info
is_active_in mitochondrion	IBA Inferred from Biological aspect of Ancestor more info
located_in mitochondrion	IDA Inferred from Direct Assay more info
located_in mitochondrion	ISS Inferred from Sequence or Structural Similarity more info	PubMed

General protein information

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Preferred Names: bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial

Names: NAD-dependent methylene tetrahydrofolate dehydrogenase cyclohydrolase

NP_001397121.1

EC 1.5.1.15

EC 3.5.4.9

NP_006627.2

EC 1.5.1.15

EC 3.5.4.9

XP_006711987.1

EC 1.5.1.15

EC 3.5.4.9

XP_054196197.1

EC 1.5.1.15

EC 3.5.4.9

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_029162.2 RefSeqGene

Range

5002..23952

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001410192.1 → NP_001397121.1 bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform B

Status: REVIEWED

Source sequence(s)

AC073263

Related

ENSP00000503701.1, ENST00000679055.1
NM_006636.4 → NP_006627.2 bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform A precursor

See identical proteins and their annotated locations for NP_006627.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the shorter transcript and is the protein-coding transcript.

Source sequence(s)

AC073263, BC017054, BX475613, CB124593

Consensus CDS

CCDS1935.2

UniProtKB/Swiss-Prot

P13995, Q53G90, Q53GV5, Q53S36, Q7Z650

UniProtKB/TrEMBL

B2R7W0

Related

ENSP00000377617.2, ENST00000394053.7

Conserved Domains (3) summary

cd01080
Location:150 → 329

NAD_bind_m-THF_DH_Cyclohyd; NADP binding domain of methylene-tetrahydrofolate dehydrogenase/cyclohydrolase

COG0190
Location:39 → 334

FolD; 5,10-methylene-tetrahydrofolate dehydrogenase/Methenyl tetrahydrofolate cyclohydrolase [Coenzyme transport and metabolism]

pfam00763
Location:39 → 155

THF_DHG_CYH; Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p14 Primary Assembly

Range

74198615..74217565

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_006711924.3 → XP_006711987.1 bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform X1

See identical proteins and their annotated locations for XP_006711987.1

UniProtKB/TrEMBL

A0A7I2V482

Related

ENSP00000503927.1, ENST00000678731.1

Conserved Domains (1) summary

COG0190
Location:3 → 232

FolD; 5,10-methylene-tetrahydrofolate dehydrogenase/Methenyl tetrahydrofolate cyclohydrolase [Coenzyme transport and metabolism]