Reviewed, UniProtKB/Swiss-Prot P07954 (FUMH_HUMAN)

Names and origin

Protein names

Recommended name:
    Fumarate hydratase, mitochondrial
      Short name=Fumarase
    EC=4.2.1.2

Gene names

Name:

FH

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	510 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	Also acts as a tumor suppressor.
Catalytic activity	(S)-malate = fumarate + H2O.
Pathway	Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1.
Subunit structure	Homotetramer.
Subcellular location	Isoform Mitochondrial: Mitochondrion. Isoform Cytoplasmic: Cytoplasm.
Post-translational modification	Isoform Cytoplasmic is acetylated at position 2 By similarity.
Involvement in disease	Defects in FH are the cause of fumarase deficiency (FD) [MIM:606812]; also known as fumaricaciduria. FD is characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia. Ref.10 Ref.11 Defects in FH are the cause of multiple cutaneous and uterine leiomyomata (MCUL1) [MIM:150800]. MCUL1 is an autosomal dominant condition in which affected individuals develop benign smooth muscle tumors (leiomyomata) of the skin. Affected females also usually develop leiomyomata of the uterus (fibroids). Ref.12 Defects in FH are the cause of hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:605839]. Ref.12
Miscellaneous	There are 2 substrate binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors By similarity.
Sequence similarities	Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.

Ontologies

Keywords
Biological process	Tricarboxylic acid cycle
Cellular component	Cytoplasm Mitochondrion
Coding sequence diversity	Alternative initiation
Disease	Disease mutation Tumor suppressor
Domain	Transit peptide
Molecular function	Lyase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	fumarate metabolic process Traceable author statement. Source: ProtInc tricarboxylic acid cycle Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	mitochondrial matrix Inferred from Experiment. Source: Reactome tricarboxylic acid cycle enzyme complex Inferred from electronic annotation. Source: InterPro
Molecular function	fumarate hydratase activity Ref.5 Inferred from Experiment. Source: Reactome
Complete GO annotation...

Alternative products

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

Isoform Mitochondrial (identifier: P07954-1)

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 Cytoplasmic (identifier: P07954-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-43: Missing.

Note: Initiator Met-1 is removed. Contains a N-acetylalanine at position 2 (By similarity).

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 44

44

Mitochondrion By similarity

Chain

45 – 510

466

Fumarate hydratase, mitochondrial

PRO_0000010319

Regions

Region

176 – 179

4

B site By similarity

Region

186 – 188

3

Substrate binding By similarity

Sites

Binding site

147

1

Substrate By similarity

Amino acid modifications

Modified residue

66

1

N6-acetyllysine Ref.9

Modified residue

80

1

N6-acetyllysine Ref.9

Modified residue

94

1

N6-acetyllysine Ref.9

Modified residue

115

1

N6-acetyllysine By similarity

Modified residue

256

1

N6-acetyllysine Ref.9

Modified residue

292

1

N6-acetyllysine Ref.9

Modified residue

477

1

N6-acetyllysine By similarity

Modified residue

491

1

Phosphotyrosine Ref.7

Natural variations

Alternative sequence

1 – 43

43

Missing in isoform Cytoplasmic.

VSP_018965

Natural variant

107

1

N → T in MCUL1. Ref.12

VAR_013497

Natural variant

117

1

A → P in MCUL1. Ref.12

VAR_013498

Natural variant

180

1

H → R in MCUL1. Ref.12

VAR_013499

Natural variant

185

1

Q → R in MCUL1. Ref.12

VAR_013500

Natural variant

230

1

K → R in FD and MCUL1. Ref.11 Ref.12

VAR_002445

Natural variant

233

1

R → H in MCUL1. dbSNP rs28933069. Ref.12

VAR_013501

Natural variant

282

1

G → V in MCUL1. Ref.12

VAR_013502

Natural variant

308

1

A → T in FD. Ref.10 Ref.11

VAR_002446

Natural variant

312

1

F → C in FD. Ref.11

VAR_002447

Natural variant

328

1

M → R in HLRCC. Ref.12

VAR_013503

Natural variant

425

1

D → V in FD. Ref.11

VAR_002448

Secondary structure

1

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510

Helix Strand Turn

Details...

Beta strand

50 – 53

4

Beta strand

60 – 63

4

Helix

71 – 78

8

Helix

90 – 95

6

Helix

99 – 106

8

Helix

107 – 109

3

Helix

114 – 128

15

Helix

133 – 135

3

Beta strand

139 – 141

3

Helix

148 – 164

17

Helix

177 – 181

5

Turn

182 – 184

3

Helix

187 – 205

19

Helix

212 – 224

13

Turn

225 – 227

3

Helix

252 – 264

13

Turn

267 – 269

3

Beta strand

270 – 272

3

Helix

290 – 300

11

Helix

311 – 316

6

Helix

319 – 324

6

Helix

328 – 344

17

Helix

375 – 387

13

Helix

391 – 395

5

Helix

409 – 422

14

Helix

426 – 433

8

Helix

442 – 451

10

Helix

454 – 459

6

Turn

460 – 462

3

Helix

466 – 477

12

Helix

482 – 488

7

Helix

494 – 500

7

Helix

503 – 505

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform Mitochondrial [UniParc]. Last modified October 1, 1996. Version 3. Checksum: 86F91F95DC046F64	FASTA	510	54,637
	10 20 30 40 50 60 MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF RIEYDTFGEL 70 80 90 100 110 120 KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK RAAAEVNQDY GLDPKIANAI 130 140 150 160 170 180 MKAADEVAEG KLNDHFPLVV WQTGSGTQTN MNVNEVISNR AIEMLGGELG SKIPVHPNDH 190 200 210 220 230 240 VNKSQSSNDT FPTAMHIAAA IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV 250 260 270 280 290 300 PLTLGQEFSG YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL 310 320 330 340 350 360 TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR SGLGELILPE 370 380 390 400 410 420 NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN GHFELNVFKP MMIKNVLHSA 430 440 450 460 470 480 RLLGDASVSF TENCVVGIQA NTERINKLMN ESLMLVTALN PHIGYDKAAK IAKTAHKNGS 490 500 510 TLKETAIELG YLTAEQFDEW VKPKDMLGPK
	Isoform Cytoplasmic. Checksum: 5E1AC7903B062540	FASTA	467	50,213
	10 20 30 40 50 60 MASQNSFRIE YDTFGELKVP NDKYYGAQTV RSTMNFKIGG VTERMPTPVI KAFGILKRAA 70 80 90 100 110 120 AEVNQDYGLD PKIANAIMKA ADEVAEGKLN DHFPLVVWQT GSGTQTNMNV NEVISNRAIE 130 140 150 160 170 180 MLGGELGSKI PVHPNDHVNK SQSSNDTFPT AMHIAAAIEV HEVLLPGLQK LHDALDAKSK 190 200 210 220 230 240 EFAQIIKIGR THTQDAVPLT LGQEFSGYVQ QVKYAMTRIK AAMPRIYELA AGGTAVGTGL 250 260 270 280 290 300 NTRIGFAEKV AAKVAALTGL PFVTAPNKFE ALAAHDALVE LSGAMNTTAC SLMKIANDIR 310 320 330 340 350 360 FLGSGPRSGL GELILPENEP GSSIMPGKVN PTQCEAMTMV AAQVMGNHVA VTVGGSNGHF 370 380 390 400 410 420 ELNVFKPMMI KNVLHSARLL GDASVSFTEN CVVGIQANTE RINKLMNESL MLVTALNPHI 430 440 450 460 GYDKAAKIAK TAHKNGSTLK ETAIELGYLT AEQFDEWVKP KDMLGPK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Gellera C., Baratta S., Cavadini P., Invernizzi F., Lamantea E., Didonato S., Taroni F. Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"Complete cDNA sequence of the human fumarase." Bourgeron T., Parfait B., Chretien D., Rotig A., Munnich A., Rustin P. Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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: Brain and Uterus.
[5]	"Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver." Kinsella B.T., Doonan S. Biosci. Rep. 6:921-929(1986) [PubMed: 3828494] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 44-510. Tissue: Liver.
[6]	Lubec G., Afjehi-Sadat L. Submitted (MAR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 269-286 AND 422-444, MASS SPECTROMETRY. Tissue: Brain and Cajal-Retzius cell.
[7]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-491, MASS SPECTROMETRY.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"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-66; LYS-80; LYS-94; LYS-256 AND LYS-292, MASS SPECTROMETRY.
[10]	"Identification of a molecular defect in a fumarase deficient patient and mapping of the fumarase gene." Coughlin E.M., Chalmers R.A., Slaugenhaupt S.A., Gusella J.F., Shih V.E., Ramesh V. Am. J. Hum. Genet. 53:A896-A896(1993) Cited for: VARIANT FD THR-308.
[11]	"Molecular analysis and prenatal diagnosis of human fumarase deficiency." Coughlin E.M., Christensen E., Kunz P.L., Krishnamoorthy K.S., Walker V., Dennis N.R., Chalmers R.A., Elpeleg O.N., Whelan D., Pollitt R.J., Ramesh V., Mandell R., Shih V.E. Mol. Genet. Metab. 63:254-262(1998) [PubMed: 9635293] [Abstract] Cited for: VARIANTS FD ARG-230; THR-308; CYS-312 AND VAL-425.
[12]	"Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer." Tomlinson I.P.M., Alam N.A., Rowan A.J., Barclay E., Jaeger E.E.M., Kelsell D., Leigh I., Gorman P., Lamlum H., Rahman S., Roylance R.R., Olpin S., Bevan S., Barker K., Hearle N., Houlston R.S., Kiuru M., Lehtonen R. , Karhu A., Vilkki S., Laiho P., Eklund C., Vierimaa O., Aittomaeki K., Hietala M., Sistonen P., Paetau A., Salovaara R., Herva R., Launonen V., Aaltonen L.A. Nat. Genet. 30:406-410(2002) [PubMed: 11865300] [Abstract] Cited for: VARIANTS MCUL1 THR-107; PRO-117; ARG-180; ARG-185; ARG-230; HIS-233 AND VAL-282, VARIANT HLRCC ARG-328.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U59309 mRNA. Translation: AAB66354.1.
U48857 mRNA. Translation: AAD00071.1.
BT009839 mRNA. Translation: AAP88841.1.
BC003108 mRNA. Translation: AAH03108.1.
BC017444 mRNA. Translation: AAH17444.1.
M15502 mRNA. Translation: AAA52483.1.

IPI

IPI00296053.
IPI00759715.

PIR

UFHUM. S06213.

RefSeq

NP_000134.2.

UniGene

Hs.592490

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3E04	X-ray	1.95	A/B/C/D	44-510	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P07954. 4 interactions.

STRING

P07954.

PTM databases

PhosphoSite

P07954.

2-D gel databases

SWISS-2DPAGE

P07954.

REPRODUCTION-2DPAGE

IPI00296053.

Proteomic databases

PRIDE

P07954.

Genome annotation databases

Ensembl

ENST00000366560; ENSP00000355518; ENSG00000091483; Homo sapiens. [Genome view]

GeneID

2271.

KEGG

hsa:2271.

UCSC

uc001hyx.1. human.

Organism-specific databases

CTD

2271.

GeneCards

GC01M239746.

H-InvDB

HIX0001737.

HGNC

HGNC:3700. FH.

HPA

CAB017785.

MIM

136850. gene.
150800. phenotype.
605839. phenotype.
606812. phenotype.

Orphanet

24. Fumaric aciduria.
523. Leiomyomatosis, familial.

PharmGKB

PA29261.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG07459.

HOGENOM

HBG284369.

HOVERGEN

P07954.

InParanoid

P07954.

OMA

RIEKDTM.

OrthoDB

EOG9909W2.

PhylomeDB

P07954.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000091483-MONOMER.

BRENDA

4.2.1.2. 247.

Reactome

REACT_1046. Pyruvate metabolism and TCA cycle.
REACT_1505. Integration of energy metabolism.
REACT_15380. Diabetes pathways.

Gene expression databases

ArrayExpress

P07954.

Bgee

P07954.

CleanEx

HS_FH.

Genevestigator

P07954.

GermOnline

ENSG00000091483. Homo sapiens.

Family and domain databases

InterPro

IPR005677. Fum_hydII.
IPR018951. Fumarase_C_C.
IPR000362. Fumarate_lyase.
IPR020557. Fumarate_lyase_CS.
IPR008948. L-Aspartase-like.
[Graphical view]

Pfam

PF10415. FumaraseC_C. 1 hit.
PF00206. Lyase_1. 1 hit.
[Graphical view]

PRINTS

PR00149. FUMRATELYASE.

PROSITE

PS00163. FUMARATE_LYASES. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

9235.

SOURCE

Search...

Entry information

Entry name

FUMH_HUMAN

Accession

Primary (citable) accession number: P07954

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1988
Last sequence update:	October 1, 1996
Last modified:	January 19, 2010
This is version 127 of the entry and version 3 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.