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P07954 (FUMH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 170. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Fumarate hydratase, mitochondrial

Short name=Fumarase
EC=4.2.1.2
Gene names
Name:FH
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length510 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Also acts as a tumor suppressor. HAMAP-Rule MF_00743

Catalytic activity

(S)-malate = fumarate + H2O. HAMAP-Rule MF_00743

Pathway

Carbohydrate metabolism; tricarboxylic acid cycle; (S)-malate from fumarate: step 1/1. HAMAP-Rule MF_00743

Subunit structure

Homotetramer. Ref.11

Subcellular location

Isoform Mitochondrial: Mitochondrion Ref.9.

Isoform Cytoplasmic: Cytoplasm Ref.9.

Tissue specificity

Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology. Ref.9

Involvement in disease

Fumarase deficiency (FHD) [MIM:606812]: Characterized by progressive encephalopathy, developmental delay, hypotonia, cerebral atrophy and lactic and pyruvic acidemia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12 Ref.13

Hereditary leiomyomatosis and renal cell cancer (HLRCC) [MIM:150800]: A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14

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.

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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 4444Mitochondrion By similarity
Chain45 – 510466Fumarate hydratase, mitochondrial HAMAP-Rule MF_00743
PRO_0000010319

Regions

Region176 – 1794B site By similarity
Region186 – 1883Substrate binding By similarity

Sites

Binding site1471Substrate By similarity

Amino acid modifications

Modified residue611N6-acetyllysine; alternate By similarity
Modified residue611N6-succinyllysine; alternate By similarity
Modified residue661N6-acetyllysine; alternate Ref.7
Modified residue661N6-succinyllysine; alternate By similarity
Modified residue801N6-acetyllysine; alternate Ref.7
Modified residue801N6-succinyllysine; alternate By similarity
Modified residue941N6-acetyllysine Ref.7
Modified residue1151N6-acetyllysine; alternate By similarity
Modified residue1151N6-succinyllysine; alternate By similarity
Modified residue1221N6-acetyllysine; alternate By similarity
Modified residue1221N6-succinyllysine; alternate By similarity
Modified residue2131N6-acetyllysine By similarity
Modified residue2231N6-acetyllysine; alternate By similarity
Modified residue2231N6-succinyllysine; alternate By similarity
Modified residue2561N6-acetyllysine Ref.7
Modified residue2921N6-acetyllysine; alternate Ref.7
Modified residue2921N6-succinyllysine; alternate By similarity
Modified residue4671N6-succinyllysine By similarity
Modified residue4731N6-succinyllysine By similarity
Modified residue5021N6-acetyllysine By similarity

Natural variations

Alternative sequence1 – 4343Missing in isoform Cytoplasmic.
VSP_018965
Natural variant1071N → T in HLRCC. Ref.14
VAR_013497
Natural variant1171A → P in HLRCC. Ref.14
VAR_013498
Natural variant1801H → R in HLRCC. Ref.14
VAR_013499
Natural variant1851Q → R in HLRCC. Ref.14
VAR_013500
Natural variant2301K → R in FHD and HLRCC. Ref.13 Ref.14
VAR_002445
Natural variant2331R → H in HLRCC. Ref.14
Corresponds to variant rs28933069 [ dbSNP | Ensembl ].
VAR_013501
Natural variant2821G → V in HLRCC. Ref.14
VAR_013502
Natural variant3081A → T in FHD. Ref.12 Ref.13
VAR_002446
Natural variant3121F → C in FHD. Ref.13
VAR_002447
Natural variant3281M → R in HLRCC. Ref.14
VAR_013503
Natural variant4251D → V in FHD. Ref.13
VAR_002448

Secondary structure

................................................................. 510
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform Mitochondrial [UniParc].

Last modified October 1, 1996. Version 3.
Checksum: 86F91F95DC046F64

FASTA51054,637
        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 

« Hide

Isoform Cytoplasmic [UniParc].

Checksum: 5E1AC7903B062540
Show »

FASTA46750,213

References

« Hide '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] [Europe PMC] [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] [Europe PMC] [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, IDENTIFICATION BY MASS SPECTROMETRY.
Tissue: Brain and Cajal-Retzius cell.
[7]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-66; LYS-80; LYS-94; LYS-256 AND LYS-292, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"Assessment of the red cell proteome of young patients with unexplained hemolytic anemia by two-dimensional differential in-gel electrophoresis (DIGE)."
von Lohneysen K., Scott T.M., Soldau K., Xu X., Friedman J.S.
PLoS ONE 7:E34237-E34237(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[10]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Crystal structure of human fumarate hydratase."
Structural genomics consortium (SGC)
Submitted (DEC-2012) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 44-510, SUBUNIT.
[12]"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 FHD THR-308.
[13]"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] [Europe PMC] [Abstract]
Cited for: VARIANTS FHD ARG-230; THR-308; CYS-312 AND VAL-425.
[14]"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. expand/collapse author list , 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] [Europe PMC] [Abstract]
Cited for: VARIANTS HLRCC THR-107; PRO-117; ARG-180; ARG-185; ARG-230; HIS-233; VAL-282 AND ARG-328.
+Additional computationally mapped references.

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.
PIRUFHUM. S06213.
RefSeqNP_000134.2. NM_000143.3.
UniGeneHs.592490.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3E04X-ray1.95A/B/C/D44-510[»]
ProteinModelPortalP07954.
SMRP07954. Positions 49-510.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108562. 36 interactions.
IntActP07954. 6 interactions.
MINTMINT-5005927.
STRING9606.ENSP00000355518.

PTM databases

PhosphoSiteP07954.

Polymorphism databases

DMDM1730117.

2D gel databases

REPRODUCTION-2DPAGEIPI00296053.
SWISS-2DPAGEP07954.
UCD-2DPAGEP07954.

Proteomic databases

PaxDbP07954.
PRIDEP07954.

Protocols and materials databases

DNASU2271.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000366560; ENSP00000355518; ENSG00000091483. [P07954-1]
GeneID2271.
KEGGhsa:2271.
UCSCuc001hyx.3. human. [P07954-1]

Organism-specific databases

CTD2271.
GeneCardsGC01M241660.
HGNCHGNC:3700. FH.
HPACAB017785.
HPA025770.
HPA025948.
HPA027341.
MIM136850. gene.
150800. phenotype.
606812. phenotype.
neXtProtNX_P07954.
Orphanet523. Familial leiomyomatosis.
24. Fumaric aciduria.
PharmGKBPA28139.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0114.
HOGENOMHOG000061736.
HOVERGENHBG002183.
InParanoidP07954.
KOK01679.
OMARIEKDTM.
OrthoDBEOG75J0MX.
PhylomeDBP07954.
TreeFamTF300441.

Enzyme and pathway databases

BioCycMetaCyc:ENSG00000091483-MONOMER.
BRENDA4.2.1.2. 2681.
ReactomeREACT_111217. Metabolism.
UniPathwayUPA00223; UER01007.

Gene expression databases

ArrayExpressP07954.
BgeeP07954.
CleanExHS_FH.
GenevestigatorP07954.

Family and domain databases

Gene3D1.10.275.10. 1 hit.
HAMAPMF_00743. FumaraseC.
InterProIPR005677. Fum_hydII.
IPR024083. Fumarase/histidase_N.
IPR018951. Fumarase_C_C.
IPR020557. Fumarate_lyase_CS.
IPR000362. Fumarate_lyase_fam.
IPR022761. Fumarate_lyase_N.
IPR008948. L-Aspartase-like.
[Graphical view]
PANTHERPTHR11444. PTHR11444. 1 hit.
PfamPF10415. FumaraseC_C. 1 hit.
PF00206. Lyase_1. 1 hit.
[Graphical view]
PRINTSPR00149. FUMRATELYASE.
SUPFAMSSF48557. SSF48557. 1 hit.
TIGRFAMsTIGR00979. fumC_II. 1 hit.
PROSITEPS00163. FUMARATE_LYASES. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP07954.
GenomeRNAi2271.
NextBio9235.
PROP07954.
SOURCESearch...

Entry information

Entry nameFUMH_HUMAN
AccessionPrimary (citable) accession number: P07954
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: October 1, 1996
Last modified: April 16, 2014
This is version 170 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM