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Protein

Fumarate hydratase, mitochondrial

Gene

FH

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Also acts as a tumor suppressor.

Catalytic activityi

(S)-malate = fumarate + H2O.

Pathwayi: tricarboxylic acid cycle

This protein is involved in step 1 of the subpathway that synthesizes (S)-malate from fumarate.
Proteins known to be involved in this subpathway in this organism are:
  1. Fumarate hydratase, mitochondrial (FH)
This subpathway is part of the pathway tricarboxylic acid cycle, which is itself part of Carbohydrate metabolism.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes (S)-malate from fumarate, the pathway tricarboxylic acid cycle and in Carbohydrate metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei147SubstrateBy similarity1

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Lyase

Keywords - Biological processi

Tricarboxylic acid cycle

Enzyme and pathway databases

BioCyciMetaCyc:ENSG00000091483-MONOMER.
ZFISH:ENSG00000091483-MONOMER.
BRENDAi4.2.1.2. 2681.
ReactomeiR-HSA-71403. Citric acid cycle (TCA cycle).
UniPathwayiUPA00223; UER01007.

Names & Taxonomyi

Protein namesi
Recommended name:
Fumarate hydratase, mitochondrial (EC:4.2.1.2)
Short name:
Fumarase
Gene namesi
Name:FH
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:3700. FH.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: ProtInc
  • cytosol Source: GO_Central
  • extracellular exosome Source: UniProtKB
  • mitochondrial matrix Source: Reactome
  • mitochondrion Source: UniProtKB
  • tricarboxylic acid cycle enzyme complex Source: InterPro
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Fumarase deficiency (FMRD)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy.
See also OMIM:606812
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_002445230K → R in FMRD and HLRCC. 2 PublicationsCorresponds to variant rs752232718dbSNPEnsembl.1
Natural variantiVAR_002446308A → T in FMRD. 2 PublicationsCorresponds to variant rs121913118dbSNPEnsembl.1
Natural variantiVAR_002447312F → C in FMRD. 1 Publication1
Natural variantiVAR_002448425D → V in FMRD. 1 Publication1
Hereditary leiomyomatosis and renal cell cancer (HLRCC)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.
See also OMIM:150800
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_013497107N → T in HLRCC. 1 PublicationCorresponds to variant rs121913121dbSNPEnsembl.1
Natural variantiVAR_013498117A → P in HLRCC. 1 Publication1
Natural variantiVAR_013499180H → R in HLRCC. 1 Publication1
Natural variantiVAR_013500185Q → R in HLRCC. 1 PublicationCorresponds to variant rs779707997dbSNPEnsembl.1
Natural variantiVAR_002445230K → R in FMRD and HLRCC. 2 PublicationsCorresponds to variant rs752232718dbSNPEnsembl.1
Natural variantiVAR_013501233R → H in HLRCC. 1 PublicationCorresponds to variant rs28933069dbSNPEnsembl.1
Natural variantiVAR_013502282G → V in HLRCC. 1 Publication1
Natural variantiVAR_013503328M → R in HLRCC. 1 Publication1

Keywords - Diseasei

Disease mutation, Tumor suppressor

Organism-specific databases

DisGeNETi2271.
MalaCardsiFH.
MIMi150800. phenotype.
606812. phenotype.
OpenTargetsiENSG00000091483.
Orphaneti24. Fumaric aciduria.
523. Hereditary leiomyomatosis and renal cell cancer.
29072. Hereditary pheochromocytoma-paraganglioma.
PharmGKBiPA28139.

Polymorphism and mutation databases

BioMutaiFH.
DMDMi1730117.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 44MitochondrionBy similarityAdd BLAST44
ChainiPRO_000001031945 – 510Fumarate hydratase, mitochondrialAdd BLAST466
Isoform Cytoplasmic (identifier: P07954-2)
Initiator methionineiRemovedBy similarity

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei61N6-acetyllysine; alternateBy similarity1
Modified residuei61N6-succinyllysine; alternateBy similarity1
Modified residuei66N6-acetyllysine; alternateCombined sources1
Modified residuei66N6-succinyllysine; alternateBy similarity1
Modified residuei80N6-acetyllysine; alternateCombined sources1
Modified residuei80N6-succinyllysine; alternateBy similarity1
Modified residuei85PhosphothreonineBy similarity1
Modified residuei90PhosphothreonineCombined sources1
Modified residuei94N6-acetyllysineCombined sources1
Modified residuei115N6-acetyllysine; alternateBy similarity1
Modified residuei115N6-succinyllysine; alternateBy similarity1
Modified residuei122N6-acetyllysine; alternateBy similarity1
Modified residuei122N6-succinyllysine; alternateBy similarity1
Modified residuei213N6-acetyllysineBy similarity1
Modified residuei223N6-acetyllysine; alternateBy similarity1
Modified residuei223N6-succinyllysine; alternateBy similarity1
Modified residuei256N6-acetyllysineCombined sources1
Modified residuei292N6-acetyllysine; alternateCombined sources1
Modified residuei292N6-succinyllysine; alternateBy similarity1
Modified residuei366PhosphoserineCombined sources1
Modified residuei467N6-succinyllysineBy similarity1
Modified residuei473N6-succinyllysineBy similarity1
Modified residuei502N6-acetyllysineBy similarity1
Isoform Cytoplasmic (identifier: P07954-2)
Modified residuei2N-acetylalanine By similarityBy similarity1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP07954.
MaxQBiP07954.
PaxDbiP07954.
PeptideAtlasiP07954.
PRIDEiP07954.
TopDownProteomicsiP07954-2. [P07954-2]

2D gel databases

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

PTM databases

iPTMnetiP07954.
PhosphoSitePlusiP07954.
SwissPalmiP07954.

Expressioni

Tissue specificityi

Expressed in red blood cells; underexpressed in red blood cells (cytoplasm) of patients with hereditary non-spherocytic hemolytic anemia of unknown etiology.1 Publication

Gene expression databases

BgeeiENSG00000091483.
CleanExiHS_FH.
ExpressionAtlasiP07954. baseline and differential.
GenevisibleiP07954. HS.

Organism-specific databases

HPAiCAB017785.
HPA025770.
HPA025948.
HPA027341.

Interactioni

Subunit structurei

Homotetramer.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
PIM1P113093EBI-1050358,EBI-696621

Protein-protein interaction databases

BioGridi108562. 77 interactors.
DIPiDIP-46920N.
IntActiP07954. 8 interactors.
MINTiMINT-5005927.
STRINGi9606.ENSP00000355518.

Structurei

Secondary structure

1510
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi50 – 55Combined sources6
Beta strandi58 – 63Combined sources6
Helixi70 – 78Combined sources9
Helixi84 – 86Combined sources3
Helixi90 – 106Combined sources17
Helixi107 – 110Combined sources4
Helixi114 – 128Combined sources15
Helixi133 – 135Combined sources3
Beta strandi139 – 142Combined sources4
Helixi147 – 164Combined sources18
Helixi177 – 181Combined sources5
Turni182 – 184Combined sources3
Helixi187 – 205Combined sources19
Helixi207 – 224Combined sources18
Turni225 – 227Combined sources3
Beta strandi229 – 234Combined sources6
Beta strandi237 – 243Combined sources7
Helixi244 – 264Combined sources21
Turni267 – 269Combined sources3
Beta strandi270 – 272Combined sources3
Turni277 – 279Combined sources3
Helixi289 – 301Combined sources13
Helixi311 – 316Combined sources6
Helixi319 – 345Combined sources27
Beta strandi349 – 352Combined sources4
Beta strandi366 – 368Combined sources3
Helixi375 – 399Combined sources25
Helixi409 – 433Combined sources25
Helixi435 – 437Combined sources3
Helixi442 – 451Combined sources10
Helixi454 – 459Combined sources6
Helixi460 – 463Combined sources4
Helixi465 – 478Combined sources14
Helixi482 – 488Combined sources7
Helixi494 – 500Combined sources7
Helixi503 – 505Combined sources3
Beta strandi506 – 508Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3E04X-ray1.95A/B/C/D44-510[»]
5D6BX-ray2.10A49-510[»]
ProteinModelPortaliP07954.
SMRiP07954.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP07954.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni176 – 179B siteBy similarity4
Regioni186 – 188Substrate bindingBy similarity3

Sequence similaritiesi

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1317. Eukaryota.
COG0114. LUCA.
GeneTreeiENSGT00390000002779.
HOGENOMiHOG000061736.
HOVERGENiHBG002183.
InParanoidiP07954.
KOiK01679.
OMAiFAYLKKA.
OrthoDBiEOG091G05UL.
PhylomeDBiP07954.
TreeFamiTF300441.

Family and domain databases

Gene3Di1.10.275.10. 1 hit.
HAMAPiMF_00743. FumaraseC. 1 hit.
InterProiIPR005677. 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]
PANTHERiPTHR11444. PTHR11444. 1 hit.
PfamiPF10415. FumaraseC_C. 1 hit.
PF00206. Lyase_1. 1 hit.
[Graphical view]
PRINTSiPR00149. FUMRATELYASE.
SUPFAMiSSF48557. SSF48557. 1 hit.
TIGRFAMsiTIGR00979. fumC_II. 1 hit.
PROSITEiPS00163. FUMARATE_LYASES. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform Mitochondrial (identifier: P07954-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MYRALRLLAR SRPLVRAPAA ALASAPGLGG AAVPSFWPPN AARMASQNSF
60 70 80 90 100
RIEYDTFGEL KVPNDKYYGA QTVRSTMNFK IGGVTERMPT PVIKAFGILK
110 120 130 140 150
RAAAEVNQDY GLDPKIANAI MKAADEVAEG KLNDHFPLVV WQTGSGTQTN
160 170 180 190 200
MNVNEVISNR AIEMLGGELG SKIPVHPNDH VNKSQSSNDT FPTAMHIAAA
210 220 230 240 250
IEVHEVLLPG LQKLHDALDA KSKEFAQIIK IGRTHTQDAV PLTLGQEFSG
260 270 280 290 300
YVQQVKYAMT RIKAAMPRIY ELAAGGTAVG TGLNTRIGFA EKVAAKVAAL
310 320 330 340 350
TGLPFVTAPN KFEALAAHDA LVELSGAMNT TACSLMKIAN DIRFLGSGPR
360 370 380 390 400
SGLGELILPE NEPGSSIMPG KVNPTQCEAM TMVAAQVMGN HVAVTVGGSN
410 420 430 440 450
GHFELNVFKP MMIKNVLHSA RLLGDASVSF TENCVVGIQA NTERINKLMN
460 470 480 490 500
ESLMLVTALN PHIGYDKAAK IAKTAHKNGS TLKETAIELG YLTAEQFDEW
510
VKPKDMLGPK
Length:510
Mass (Da):54,637
Last modified:October 1, 1996 - v3
Checksum:i86F91F95DC046F64
GO
Isoform Cytoplasmic (identifier: P07954-2) [UniParc]FASTAAdd to basket

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

Show »
Length:467
Mass (Da):50,213
Checksum:i5E1AC7903B062540
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_013497107N → T in HLRCC. 1 PublicationCorresponds to variant rs121913121dbSNPEnsembl.1
Natural variantiVAR_013498117A → P in HLRCC. 1 Publication1
Natural variantiVAR_013499180H → R in HLRCC. 1 Publication1
Natural variantiVAR_013500185Q → R in HLRCC. 1 PublicationCorresponds to variant rs779707997dbSNPEnsembl.1
Natural variantiVAR_002445230K → R in FMRD and HLRCC. 2 PublicationsCorresponds to variant rs752232718dbSNPEnsembl.1
Natural variantiVAR_013501233R → H in HLRCC. 1 PublicationCorresponds to variant rs28933069dbSNPEnsembl.1
Natural variantiVAR_013502282G → V in HLRCC. 1 Publication1
Natural variantiVAR_002446308A → T in FMRD. 2 PublicationsCorresponds to variant rs121913118dbSNPEnsembl.1
Natural variantiVAR_002447312F → C in FMRD. 1 Publication1
Natural variantiVAR_013503328M → R in HLRCC. 1 Publication1
Natural variantiVAR_002448425D → V in FMRD. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0189651 – 43Missing in isoform Cytoplasmic. CuratedAdd BLAST43

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59309 mRNA. Translation: AAB66354.1.
U48857 mRNA. Translation: AAD00071.1.
BT009839 mRNA. Translation: AAP88841.1.
AK312415 mRNA. Translation: BAG35325.1.
CH471098 Genomic DNA. Translation: EAW70092.1.
BC003108 mRNA. Translation: AAH03108.1.
BC017444 mRNA. Translation: AAH17444.1.
M15502 mRNA. Translation: AAA52483.1.
CCDSiCCDS1617.1. [P07954-1]
PIRiS06213. UFHUM.
RefSeqiNP_000134.2. NM_000143.3. [P07954-1]
UniGeneiHs.592490.

Genome annotation databases

EnsembliENST00000366560; ENSP00000355518; ENSG00000091483. [P07954-1]
GeneIDi2271.
KEGGihsa:2271.
UCSCiuc001hyx.4. human. [P07954-1]

Keywords - Coding sequence diversityi

Alternative initiation

Cross-referencesi

Web resourcesi

TCA Cycle Gene Mutation Database
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U59309 mRNA. Translation: AAB66354.1.
U48857 mRNA. Translation: AAD00071.1.
BT009839 mRNA. Translation: AAP88841.1.
AK312415 mRNA. Translation: BAG35325.1.
CH471098 Genomic DNA. Translation: EAW70092.1.
BC003108 mRNA. Translation: AAH03108.1.
BC017444 mRNA. Translation: AAH17444.1.
M15502 mRNA. Translation: AAA52483.1.
CCDSiCCDS1617.1. [P07954-1]
PIRiS06213. UFHUM.
RefSeqiNP_000134.2. NM_000143.3. [P07954-1]
UniGeneiHs.592490.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3E04X-ray1.95A/B/C/D44-510[»]
5D6BX-ray2.10A49-510[»]
ProteinModelPortaliP07954.
SMRiP07954.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108562. 77 interactors.
DIPiDIP-46920N.
IntActiP07954. 8 interactors.
MINTiMINT-5005927.
STRINGi9606.ENSP00000355518.

PTM databases

iPTMnetiP07954.
PhosphoSitePlusiP07954.
SwissPalmiP07954.

Polymorphism and mutation databases

BioMutaiFH.
DMDMi1730117.

2D gel databases

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

Proteomic databases

EPDiP07954.
MaxQBiP07954.
PaxDbiP07954.
PeptideAtlasiP07954.
PRIDEiP07954.
TopDownProteomicsiP07954-2. [P07954-2]

Protocols and materials databases

DNASUi2271.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000366560; ENSP00000355518; ENSG00000091483. [P07954-1]
GeneIDi2271.
KEGGihsa:2271.
UCSCiuc001hyx.4. human. [P07954-1]

Organism-specific databases

CTDi2271.
DisGeNETi2271.
GeneCardsiFH.
GeneReviewsiFH.
HGNCiHGNC:3700. FH.
HPAiCAB017785.
HPA025770.
HPA025948.
HPA027341.
MalaCardsiFH.
MIMi136850. gene.
150800. phenotype.
606812. phenotype.
neXtProtiNX_P07954.
OpenTargetsiENSG00000091483.
Orphaneti24. Fumaric aciduria.
523. Hereditary leiomyomatosis and renal cell cancer.
29072. Hereditary pheochromocytoma-paraganglioma.
PharmGKBiPA28139.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1317. Eukaryota.
COG0114. LUCA.
GeneTreeiENSGT00390000002779.
HOGENOMiHOG000061736.
HOVERGENiHBG002183.
InParanoidiP07954.
KOiK01679.
OMAiFAYLKKA.
OrthoDBiEOG091G05UL.
PhylomeDBiP07954.
TreeFamiTF300441.

Enzyme and pathway databases

UniPathwayiUPA00223; UER01007.
BioCyciMetaCyc:ENSG00000091483-MONOMER.
ZFISH:ENSG00000091483-MONOMER.
BRENDAi4.2.1.2. 2681.
ReactomeiR-HSA-71403. Citric acid cycle (TCA cycle).

Miscellaneous databases

EvolutionaryTraceiP07954.
GenomeRNAii2271.
PROiP07954.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000091483.
CleanExiHS_FH.
ExpressionAtlasiP07954. baseline and differential.
GenevisibleiP07954. HS.

Family and domain databases

Gene3Di1.10.275.10. 1 hit.
HAMAPiMF_00743. FumaraseC. 1 hit.
InterProiIPR005677. 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]
PANTHERiPTHR11444. PTHR11444. 1 hit.
PfamiPF10415. FumaraseC_C. 1 hit.
PF00206. Lyase_1. 1 hit.
[Graphical view]
PRINTSiPR00149. FUMRATELYASE.
SUPFAMiSSF48557. SSF48557. 1 hit.
TIGRFAMsiTIGR00979. fumC_II. 1 hit.
PROSITEiPS00163. FUMARATE_LYASES. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiFUMH_HUMAN
AccessioniPrimary (citable) accession number: P07954
Secondary accession number(s): B1ANK7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: October 1, 1996
Last modified: November 30, 2016
This is version 198 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

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).By similarity

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.