Reviewed, UniProtKB/Swiss-Prot Q6UB35 (C1TM_HUMAN)

Names and origin

Protein names

Recommended name:
    Monofunctional C1-tetrahydrofolate synthase, mitochondrial
    EC=6.3.4.3
Alternative name(s):
    Formyltetrahydrofolate synthetase

Gene names

Name:	MTHFD1L
Synonyms:	FTHFSDC1

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	978 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)

Function	May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism in embryonic an transformed cells complementing thus the enzymatic activities of MTHFD2 By similarity. Ref.5
Catalytic activity	ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate.
Pathway	One-carbon metabolism; tetrahydrofolate interconversion.
Subunit structure	Homodimer. Ref.5
Subcellular location	Mitochondrion Ref.1.
Tissue specificity	Detected in most tissues, highest expression found in placenta, thymus and brain. Low expression is found in liver and skeletal muscle. Up-regulated in colon adenocarcinoma. Ref.1 Ref.2
Domain	This monofunctional enzyme consists of two major domains: an N-terminal inactive methylene-THF dehydrogenase and cyclohydrolase domain and an active larger formyl-THF synthetase C-terminal domain.
Miscellaneous	May participate in the progression of colorectal cancer by conferring growth advantage. Could be a new molecular target for cancer therapy.
Sequence similarities	In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family. In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.
Caution	This enzyme lacks methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5) and ethenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9) activities. An enzyme performing these two complementary activities has not been found in adult mitochondrial tissues; MTHFD2, which performs these two activities, was found in developing tissues only. Was thought to be a trifunctional enzyme (Ref.1) but only a formyltetrahydrofolate synthetase activity was detected and not a dehydrogenase/cyclohydrogenase activity.
Biophysicochemical properties	Kinetic parameters: KM=500 µM for THF monoglutamate KM=16 µM for THF triglutamate KM=3.6 µM for THF pentaglutamate

Ontologies

Keywords
Biological process	One-carbon metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transit peptide
Ligand	ATP-binding Nucleotide-binding
Molecular function	Ligase
PTM	Acetylation
Technical term	Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	folic acid and derivative biosynthetic process Inferred from electronic annotation. Source: InterPro formate metabolic process Ref.5 Inferred from direct assay. Source: UniProtKB one-carbon metabolic process Inferred from electronic annotation. Source: UniProtKB-KW tetrahydrofolate metabolic process Ref.1 Inferred from direct assay. Source: UniProtKB
Cellular component	mitochondrion Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Ref.5 Inferred from direct assay. Source: UniProtKB formate-tetrahydrofolate ligase activity Ref.1 Inferred from direct assay. Source: UniProtKB protein homodimerization activity Ref.5 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CASP4	P49662	1	EBI-1046835,EBI-1057327
MAGED1	Q9Y5V3	1	EBI-1046835,EBI-716006
WDR8	Q9P2S5	1	EBI-1046835,EBI-1054904

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q6UB35-1)

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.

Isoform 2 (identifier: Q6UB35-2)

The sequence of this isoform differs from the canonical sequence as follows:
     261-275: LHEADIVVLGSPKPE → TESRSVTRLECRRVI
     276-978: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 31	31	Mitochondrion Ref.5
	Chain	32 – 978	947	Monofunctional C1-tetrahydrofolate synthase, mitochondrial		PRO_0000343177
Regions
	Nucleotide binding	423 – 430	8	ATP By similarity
	Region	31 – 348	318	Methylenetetrahydrofolate dehydrogenase and cyclohydrolase
	Region	349 – 978	630	Formyltetrahydrofolate synthetase
	Compositional bias	34 – 42	9	Poly-Gly
Amino acid modifications
	Modified residue	174	1	N6-acetyllysine Ref.11
	Modified residue	189	1	N6-acetyllysine Ref.11
Natural variations
	Alternative sequence	261 – 275	15	LHEAD…SPKPE → TESRSVTRLECRRVI in isoform 2.		VSP_034565
	Alternative sequence	276 – 978	703	Missing in isoform 2.		VSP_034566
	Natural variant	444	1	L → R in a colorectal cancer sample; somatic mutation. Ref.12		VAR_044346
Experimental info
	Sequence conflict	79	1	I → V in AAI10320. Ref.7
	Sequence conflict	870	1	R → M in BAB15009. Ref.9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 7D655CD8D2503378	FASTA	978	105,790
	10 20 30 40 50 60 MGTRLPLVLR QLRRPPQPPG PPRRLRVPCR ASSGGGGGGG GGREGLLGQR RPQDGQARSS 70 80 90 100 110 120 CSPGGRTPAA RDSIVREVIQ NSKEVLSLLQ EKNPAFKPVL AIIQAGDDNL MQEINQNLAE 130 140 150 160 170 180 EAGLNITHIC LPPDSSEAEI IDEILKINED TRVHGLALQI SENLFSNKVL NALKPEKDVD 190 200 210 220 230 240 GVTDINLGKL VRGDAHECFV SPVAKAVIEL LEKSGVNLDG KKILVVGAHG SLEAALQCLF 250 260 270 280 290 300 QRKGSMTMSI QWKTRQLQSK LHEADIVVLG SPKPEEIPLT WIQPGTTVLN CSHDFLSGKV 310 320 330 340 350 360 GCGSPRIHFG GLIEEDDVIL LAAALRIQNM VSSGRRWLRE QQHRRWRLHC LKLQPLSPVP 370 380 390 400 410 420 SDIEISRGQT PKAVDVLAKE IGLLADEIEI YGKSKAKVRL SVLERLKDQA DGKYVLVAGI 430 440 450 460 470 480 TPTPLGEGKS TVTIGLVQAL TAHLNVNSFA CLRQPSQGPT FGVKGGAAGG GYAQVIPMEE 490 500 510 520 530 540 FNLHLTGDIH AITAANNLLA AAIDTRILHE NTQTDKALYN RLVPLVNGVR EFSEIQLARL 550 560 570 580 590 600 KKLGINKTDP STLTEEEVSK FARLDIDPST ITWQRVLDTN DRFLRKITIG QGNTEKGHYR 610 620 630 640 650 660 QAQFDIAVAS EIMAVLALTD SLADMKARLG RMVVASDKSG QPVTADDLGV TGALTVLMKD 670 680 690 700 710 720 AIKPNLMQTL EGTPVFVHAG PFANIAHGNS SVLADKIALK LVGEEGFVVT EAGFGADIGM 730 740 750 760 770 780 EKFFNIKCRA SGLVPNVVVL VATVRALKMH GGGPSVTAGV PLKKEYTEEN IQLVADGCCN 790 800 810 820 830 840 LQKQIQITQL FGVPVVVALN VFKTDTRAEI DLVCELAKRA GAFDAVPCYH WSVGGKGSVD 850 860 870 880 890 900 LARAVREAAS KRSRFQFLYD VQVPIVDKIR TIAQAVYGAK DIELSPEAQA KIDRYTQQGF 910 920 930 940 950 960 GNLPICMAKT HLSLSHQPDK KGVPRDFILP ISDVRASIGA GFIYPLVGTM STMPGLPTRP 970 CFYDIDLDTE TEQVKGLF
	Isoform 2. Checksum: AA044C3A5C698249	FASTA	275	29,804
	10 20 30 40 50 60 MGTRLPLVLR QLRRPPQPPG PPRRLRVPCR ASSGGGGGGG GGREGLLGQR RPQDGQARSS 70 80 90 100 110 120 CSPGGRTPAA RDSIVREVIQ NSKEVLSLLQ EKNPAFKPVL AIIQAGDDNL MQEINQNLAE 130 140 150 160 170 180 EAGLNITHIC LPPDSSEAEI IDEILKINED TRVHGLALQI SENLFSNKVL NALKPEKDVD 190 200 210 220 230 240 GVTDINLGKL VRGDAHECFV SPVAKAVIEL LEKSGVNLDG KKILVVGAHG SLEAALQCLF 250 260 270 QRKGSMTMSI QWKTRQLQSK TESRSVTRLE CRRVI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls." Prasannan P., Pike S., Peng K., Shane B., Appling D.R. J. Biol. Chem. 278:43178-43187(2003) [PubMed: 12937168] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[2]	"A novel mitochondrial C1-tetrahydrofolate synthetase is upregulated in human colon adenocarcinoma." Sugiura T., Nagano Y., Inoue T., Hirotani K. Biochem. Biophys. Res. Commun. 315:204-211(2004) [PubMed: 15013446] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY. Tissue: Testis.
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase." Walkup A.S., Appling D.R. Arch. Biochem. Biophys. 442:196-205(2005) [PubMed: 16171773] [Abstract] Cited for: PROTEIN SEQUENCE OF 32-66, FUNCTION, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES.
[6]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 62-978 (ISOFORM 1). Tissue: Uterus.
[7]	"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] OF 79-978 (ISOFORM 1). Tissue: Cervix, Eye and Muscle.
[8]	Bienvenut W.V., Matallanas D., Cooper W.N., Kolch W. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 522-530; 564-575 AND 926-935, MASS SPECTROMETRY. Tissue: Mammary carcinoma.
[9]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 591-978 (ISOFORM 1).
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"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-174 AND LYS-189, MASS SPECTROMETRY.
[12]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ARG-444.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY374130 mRNA. Translation: AAQ82696.1. AY374131 mRNA. Translation: AAQ82697.1. AB127387 mRNA. Translation: BAD93193.1. CH471051 Genomic DNA. Translation: EAW47762.1. AL035086, AL049694, AL133260 Genomic DNA. Translation: CAI42794.1. AL133260, AL035086, AL049694 Genomic DNA. Translation: CAI95678.1. AL049694, AL035086, AL133260 Genomic DNA. Translation: CAI95774.1. AL117452 mRNA. Translation: CAB55934.1. BC008629 mRNA. Translation: AAH08629.1. Different initiation. BC017477 mRNA. Translation: AAH17477.2. BC110319 mRNA. Translation: AAI10320.1. AK024798 mRNA. Translation: BAB15009.1. Different initiation.
IPI	IPI00552054. IPI00939493.
PIR	T17244.
RefSeq	NP_056255.2.
UniGene	Hs.591343
3D structure databases
HSSP	HSSP built from PDB template 1FPM based on UniProtKB P21164.
SMR	Q6UB35. Positions 73-339, 362-976.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q6UB35. 10 interactions.
STRING	Q6UB35.
PTM databases
PhosphoSite	Q6UB35.
Proteomic databases
PRIDE	Q6UB35.
Genome annotation databases
Ensembl	ENST00000367321; ENSP00000356290; ENSG00000120254; Homo sapiens. [Genome view]
GeneID	25902.
KEGG	hsa:25902.
UCSC	uc003qoa.1. human. uc003qob.1. human.
Organism-specific databases
CTD	25902.
GeneCards	GC06P151279.
HGNC	HGNC:21055. MTHFD1L.
HPA	HPA015006.
MIM	611427. gene.
PharmGKB	PA134927803.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q6UB35.
InParanoid	Q6UB35.
OMA	PEAQSKI.
OrthoDB	EOG9KSS4W.
PhylomeDB	Q6UB35.
Enzyme and pathway databases
BRENDA	6.3.4.3. 247.
Gene expression databases
ArrayExpress	Q6UB35.
Bgee	Q6UB35.
CleanEx	HS_MTHFD1L.
Genevestigator	Q6UB35.
Family and domain databases
InterPro	IPR000559. Formate_THF_ligase. IPR020628. Formate_THF_ligase_CS. IPR016040. NAD(P)-bd_dom. IPR000672. THF_DH/CycHdrlase. IPR020630. THF_DH/CycHdrlase_cat_dom. IPR020631. THF_DH/CycHdrlase_NAD-bd_dom. [Graphical view]
Gene3D	G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.
Pfam	PF01268. FTHFS. 1 hit. PF00763. THF_DHG_CYH. 1 hit. PF02882. THF_DHG_CYH_C. 1 hit. [Graphical view]
PRINTS	PR00085. THFDHDRGNASE.
PROSITE	PS00721. FTHFS_1. 1 hit. PS00722. FTHFS_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	47370.
SOURCE	Search...

Entry information

Entry name

C1TM_HUMAN

Accession

Primary (citable) accession number: Q6UB35
Secondary accession number(s): Q2TBF3 , Q8WVW0, Q96HG8, Q9H789, Q9UFU8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 2008
Last sequence update:	July 5, 2004
Last modified:	January 19, 2010
This is version 59 of the entry and version 1 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.