Reviewed, UniProtKB/Swiss-Prot P13995 (MTDC_HUMAN)

Names and origin

Protein names

Recommended name:
    Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Including the following 2 domains:
    1- Recommended name:
            NAD-dependent methylenetetrahydrofolate dehydrogenase
              EC=1.5.1.15
    2- Recommended name:
            Methenyltetrahydrofolate cyclohydrolase
              EC=3.5.4.9

Gene names

Name:	MTHFD2
Synonyms:	NMDMC

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	350 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	5,10-methylenetetrahydrofolate + NAD+ = 5,10-methenyltetrahydrofolate + NADH. 5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate.
Cofactor	Magnesium.
Subunit structure	Homodimer.
Subcellular location	Mitochondrion.
Developmental stage	Expressed only in developing normal tissues.
Miscellaneous	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.
Sequence similarities	Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.

Ontologies

Keywords
Biological process	One-carbon metabolism
Cellular component	Mitochondrion
Domain	Transit peptide
Ligand	Magnesium NAD
Molecular function	Hydrolase Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome Multifunctional enzyme
Gene Ontology (GO)
Biological process	folic acid and derivative biosynthetic process Inferred from electronic annotation. Source: InterPro one-carbon metabolic process Inferred from electronic annotation. Source: UniProtKB-KW oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW tetrahydrofolate metabolic process Inferred from direct assay. Source: UniProtKB
Cellular component	mitochondrion Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	magnesium ion binding Inferred from direct assay. Source: UniProtKB methenyltetrahydrofolate cyclohydrolase activity Inferred from sequence or structural similarity. Source: UniProtKB methylenetetrahydrofolate dehydrogenase (NAD+) activity Inferred from direct assay. Source: UniProtKB methylenetetrahydrofolate dehydrogenase (NADP+) activity Inferred from direct assay. Source: UniProtKB phosphate binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 35	35	Mitochondrion By similarity
	Chain	36 – 350	315	Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial		PRO_0000034049
Amino acid modifications
	Modified residue	50	1	N6-acetyllysine Ref.6
Experimental info
	Sequence conflict	75	1	V → A in BAD96546. Ref.2
	Sequence conflict	95	1	V → A in BAD96761. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P13995-1 [UniParc]. Last modified September 19, 2006. Version 2. Checksum: 4DBD263CF7BE28F4	FASTA	350	37,895
	10 20 30 40 50 60 MAATSLMSAL AARLLQPAHS CSLRLRPFHL AAVRNEAVVI SGRKLAQQIK QEVRQEVEEW 70 80 90 100 110 120 VASGNKRPHL SVILVGENPA SHSYVLNKTR AAAVVGINSE TIMKPASISE EELLNLINKL 130 140 150 160 170 180 NNDDNVDGLL VQLPLPEHID ERRICNAVSP DKDVDGFHVI NVGRMCLDQY SMLPATPWGV 190 200 210 220 230 240 WEIIKRTGIP TLGKNVVVAG RSKNVGMPIA MLLHTDGAHE RPGGDATVTI SHRYTPKEQL 250 260 270 280 290 300 KKHTILADIV ISAAGIPNLI TADMIKEGAA VIDVGINRVH DPVTAKPKLV GDVDFEGVRQ 310 320 330 340 350 KAGYITPVPG GVGPMTVAML MKNTIIAAKK VLRLEEREVL KSKELGVATN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase." Peri K.G., Belanger C., Mackenzie R.E. Nucleic Acids Res. 17:8853-8853(1989) [PubMed: 2587219] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 3-350.
[2]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver and Thyroid.
[3]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cervix and Colon.
[5]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[6]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-50, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X16396 mRNA. Translation: CAA34431.1. Different initiation.
AK222826 mRNA. Translation: BAD96546.1. Different initiation.
AK223041 mRNA. Translation: BAD96761.1. Different initiation.
AC073263 Genomic DNA. Translation: AAX93061.1. Different initiation.
BC001548 mRNA. Translation: AAH01548.2.
BC017054 mRNA. Translation: AAH17054.2.

IPI

IPI00011307.

PIR

DEHUMT. S14902.

RefSeq

NP_006627.2.

UniGene

Hs.469030

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ZN4	model	-	A/B	37-350	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P13995.

PTM databases

PhosphoSite

P13995.

Proteomic databases

PRIDE

P13995.

Genome annotation databases

Ensembl

ENST00000264090; ENSP00000264090; ENSG00000065911; Homo sapiens. [Genome view]
ENST00000394050; ENSP00000377614; ENSG00000065911; Homo sapiens. [Genome view]
ENST00000394053; ENSP00000377617; ENSG00000065911; Homo sapiens. [Genome view]
ENST00000409601; ENSP00000386542; ENSG00000065911; Homo sapiens. [Genome view]
ENST00000409804; ENSP00000386536; ENSG00000065911; Homo sapiens. [Genome view]

GeneID

10797.

KEGG

hsa:10797.

NMPDR

fig|9606.3.peg.18064.

UCSC

uc002skk.1. human.

Organism-specific databases

CTD

10797.

GeneCards

GC02P074337.

HGNC

HGNC:7434. MTHFD2.

HPA

CAB003684.

MIM

604887. gene.

PharmGKB

PA31238.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P13995.

HOVERGEN

P13995.

OMA

HSKTRDL.

Enzyme and pathway databases

BRENDA

1.5.1.15. 247.
3.5.4.9. 247.

Gene expression databases

ArrayExpress

P13995.

Bgee

P13995.

CleanEx

HS_MTHFD2.

Genevestigator

P13995.

GermOnline

ENSG00000065911. Homo sapiens.

Family and domain databases

InterPro

IPR016040. NAD(P)-bd_dom.
IPR000672. THF_DH/CycHdrlase.
[Graphical view]

Gene3D

G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

Pfam

PF00763. THF_DHG_CYH. 1 hit.
PF02882. THF_DHG_CYH_C. 1 hit.
[Graphical view]

PRINTS

PR00085. THFDHDRGNASE.

ProDom

PD002300. THFDhg/Cyc_hydro. 1 hit.
[Graphical view] [Entries sharing at least one domain]

PROSITE

PS00766. THF_DHG_CYH_1. 1 hit.
PS00767. THF_DHG_CYH_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.
DB00116. Tetrahydrofolic acid.

NextBio

41003.

SOURCE

Search...

Entry information

Entry name

MTDC_HUMAN

Accession

Primary (citable) accession number: P13995
Secondary accession number(s): Q53G90, Q53GV5, Q53S36

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 1, 1990
Last sequence update:	September 19, 2006
Last modified:	November 3, 2009
This is version 106 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.