Any feedback?
Please rate this page
(enzyme.php)
(0/150)

BRENDA support

BRENDA Home
show all | hide all No of entries

Information on EC 4.2.1.2 - fumarate hydratase and Organism(s) Homo sapiens and UniProt Accession P07954

for references in articles please use BRENDA:EC4.2.1.2
Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
     4 Lyases
         4.2 Carbon-oxygen lyases
             4.2.1 Hydro-lyases
                4.2.1.2 fumarate hydratase
Specify your search results
Select one or more organisms in this record: ?
This record set is specific for:
Homo sapiens
UNIPROT: P07954 not found.
Show additional data
Do not include text mining results
Include (text mining) results
Include results (AMENDA + additional results, but less precise)
Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
fumarase, fumarate hydratase, fumarase c, class ii fumarase, lmfh-2, scfumc, slfumc, mmcbc, lmfh-1, stfumc, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
fumarase
fumarate hydratase
-
-
hydratase, fumarate
-
-
-
-
L-malate hydro-lyase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
elimination
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
(S)-malate hydro-lyase (fumarate-forming)
-
CAS REGISTRY NUMBER
COMMENTARY hide
9032-88-6
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
L-malate
fumarate + H2O
show the reaction diagram
-
-
-
?
fumarate + H2O
L-malate
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
fumarate + H2O
L-malate
show the reaction diagram
-
enzyme of Krebs cycle
-
r
additional information
?
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1.1 - 2
L-malate
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.041 - 150
L-malate
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.021 - 80
L-malate
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
cells from individuals with hereditary leiomyomatosis and renal cell cancer have lower fumarate hydratase enzyme activity than cells from normal controls
Manually annotated by BRENDA team
-
cells from individuals with hereditary leiomyomatosis and renal cell cancer have lower fumarate hydratase enzyme activity than cells from normal controls
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
Cos-1 cells transfected with fumarase constructs, human fumarase with either the native or cytochrome c oxidase subunit VIII mitochondrial targeting sequence is detected exclusively in mitochondria in more than 98% of the cells, while the remainder 1-2% of the cells shows varying amounts of nuclear labeling. When human fumarase is fused to the yeast mitochondrial targeting sequence, more than 50% of the cells show nuclear labeling
Manually annotated by BRENDA team
-
after both hydroxyurea or ionizing radiation treatments, is localized in the nucleus after DNA damage
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
-
fumarate hydratase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarate hydratase and which is most probably independent of hypoxia-inducible factor. Cytoplasmic version of fumarate hydratase has a role in repairing DNA double-strand breaks in the nucleus. This role involves the movement of fumarate hydratase from the cytoplasm into the nucleus and depends on its enzymatic activity. When fumarate hydratase is absent from cells, its function in DNA repair can be substituted by high concentrations of one of the enzyme's products, fumaric acid. Fumarate hydratase deficiency leads to cancer because there is not enough fumaric acid in the nucleus to stimulate repair of DNA double-strand breaks. Can complement the cytosolic absence of fumarase in yeast with a DELTAfum1 chromosomal deletion
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
FUMH_HUMAN
510
0
54637
Swiss-Prot
Mitochondrion (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
135000
gel filtration, mutants H318Y and A308T
210000
gel filtration, wild-type
48000
-
mitochondrial fumarate hydratase is translated as an approximately 54000 Da precursor, which is processed upon mitochondrial transport by cleavage of the N-terminal targeting signal, resulting in a mature form of 48000 Da
50000
-
4 * 50000, SDS-PAGE
54000
-
mitochondrial fumarate hydratase is translated as an approximately 54000 Da precursor, which is processed upon mitochondrial transport by cleavage of the N-terminal targeting signal, resulting in a mature form of 48000 Da
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 53700, calculated from sequence
tetramer
4 * 53800, calculated from sequence and SDS-PAGE
homotetramer
-
4 * 50000, SDS-PAGE
additional information
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 2.1 A resolution, space group C222
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A308T
mutation associated with fumarate hydratase deficiency and hereditary leiomyomatosis and renal cell cancer. Enzyme shows severely diminished fumarase activity, and the variant is largely defective due to decreased turnover rate, while displaying Km values for L-malate similar to wild-type. The protein forms homodimers rather than homotetramers
H318Y
mutation associated with fumarate hydratase deficiency and hereditary leiomyomatosis and renal cell cancer. Enzyme shows severely diminished fumarase activity, and the variant is largely defective due to decreased turnover rate, while displaying Km values for L-malate similar to wild-type. The protein forms homodimers rather than homotetramers
A117P
-
missense mutation
A239T
-
missense mutation
A274T
-
missense mutation
A308Y
-
the mutation is associated with fumarase deficiency
A385D
-
missense mutation
C333Y
-
missense mutation
D425V
-
the mutation is associated with fumarase deficiency
E319Q
-
mutant with strongly reduced activity
E355K
-
missense mutation
E362Q
-
the mutation is associated with fumarase deficiency
F312C
-
the mutation is associated with fumarase deficiency
G282V
-
missense mutation
G397R
-
missense mutation
H135R
-
missense mutation
H180R
-
missense mutation
H318L
-
the mutation is associated with fumarase deficiency
H402C
-
the mutation is associated with fumarase deficiency
I229T
-
missense mutation
I77V
-
the mutant enzyme shows increased activity
K230R
-
missense mutation
K424R
K467R
-
missense mutation
L335P
-
missense mutation
L507P
-
missense mutation
M195T
-
missense mutation
M368T
-
the mutation is associated with hereditarymultiplecutaneous leiomyoma
M454I
-
missense mutation
N107T
-
missense mutation
N188S
-
missense mutation
N310Y
-
missense mutation
N330S
-
missense mutation detected in a patient with a bilateral renal cell cancer
N340K
-
missense mutation
N362K
-
the mutation is associated with renal cell cancer
P174R
-
missense mutation
P192L
-
missense mutation
P369S
-
the mutation is associated with fumarase deficiency
Q142K
-
missense mutation
Q185R
-
missense mutation
Q376P
-
the mutation is associated with fumarase deficiency
Q439P
-
the mutation is associated with renal cell cancer
R101P
-
the mutation is associated with renal cell cancer
R101X
-
the mutation is associated with renal cell cancer
R160G
-
missense mutation
R190H
R233C
-
the mutation is associated with renal cell cancer
R233H
-
the mutation is associated with renal cell cancer
R233L
-
the mutation is associated with renal cell cancer
R343X
-
the mutation is associated with renal cell cancer
R51E
-
missense mutation
S158I
-
missense mutation
S187L
-
missense mutation
S334R
-
the mutation is associated with hereditarymultiplecutaneous leiomyoma
S365G
-
missense mutation
S365N
-
missense mutation
S41P
-
the mutation is associated with renal cell cancer
T330P
-
missense mutation
V322D
-
missense mutation
V394L
-
missense mutation
Y465C
-
missense mutation
additional information
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
Cos-1 cells transfected with fumarase constructs, human fumarase with either the native or cytochrome c oxidase subunit VIII mitochondrial targeting sequence is detected exclusively in mitochondria in more than 98% of the cells, while the remainder 1-2% of the cells shows varying amounts of nuclear labeling. When human fumarase is fused to the yeast mitochondrial targeting sequence, more than 50% of the cells show nuclear labeling
expression in Escherichia coli
expressed in HK-2 cells and in skin fibroblasts
-
expressed in yeast FUM1 mutant strain
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
fumarate hydratase levels increase 2fold after 24 h of treatment with double-strand breaks. Is overexpressed in response to DNA damage
-
knock down of total cellular fumarate hydratase expression using specific shRNA
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
fumarate hydratase activity can be useful in the diagnosis of hereditary leiomyomatosis and renal cell cancer in cases with atypical presentation and undetectable fumarate hydratase mutations. Furthermore, fumarate hydratase activity testing is of value in laboratory investigations to elucidate the mechanism of hereditary leiomyomatosis and renal cell cancer
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Estevez, M.; Skarda, J.; Spencer, J.; Banaszak, L.; Weaver, T.M.
X-ray crystallographic and kinetic correlation of a clinically observed human fumarase mutation
Protein Sci.
11
1552-1557
2002
Homo sapiens, Escherichia coli (P05042), Escherichia coli
Manually annotated by BRENDA team
Lehtonen, R.; Kiuru, M.; Vanharanta, S.; Sjoeberg, J.; Aaltonen, L.M.; Aittomaeki, K.; Arola, J.; Butzow, R.; Eng, C.; Husgafvel-Pursiainen, K.; Isola, J.; Jaervinen, H.; Koivisto, P.; Mecklin, J.P.; Peltomaeki, P.; Salovaara, R.; Wasenius, V.M.; Karhu, A.; Launonen, V.; Nupponen, N.N.; Aaltonen, L.A.
Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors
Am. J. Pathol.
164
17-22
2004
Homo sapiens
Manually annotated by BRENDA team
Gross, K.L.; Panhuysen, C.I.; Kleinman, M.S.; Goldhammer, H.; Jones, E.S.; Nassery, N.; Stewart, E.A.; Morton, C.C.
Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies
Genes Chromosomes Cancer
41
183-190
2004
Homo sapiens
Manually annotated by BRENDA team
Alam, N.A.; Olpin, S.; Rowan, A.; Kelsell, D.; Leigh, I.M.; Tomlinson, I.P.; Weaver, T.
Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer
J. Mol. Diagn.
7
437-443
2005
Homo sapiens
Manually annotated by BRENDA team
Remes, A.M.; Filppula, S.A.; Rantala, H.; Leisti, J.; Ruokonen, A.; Sharma, S.; Juffer, A.H.; Hiltunen, J.K.
A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency
J. Mol. Med.
82
550-554
2004
Homo sapiens
Manually annotated by BRENDA team
Singh, B.; Gupta, R.S.
Mitochondrial import of human and yeast fumarase in live mammalian cells: retrograde translocation of the yeast enzyme is mainly caused by its poor targeting sequence
Biochem. Biophys. Res. Commun.
346
911-918
2006
Homo sapiens (P07954), Homo sapiens, Saccharomyces cerevisiae (P08417), Saccharomyces cerevisiae
Manually annotated by BRENDA team
Lehtonen, H.J.; Blanco, I.; Piulats, J.M.; Herva, R.; Launonen, V.; Aaltonen, L.A.
Conventional renal cancer in a patient with fumarate hydratase mutation
Hum. Pathol.
38
793-796
2007
Homo sapiens
Manually annotated by BRENDA team
Ylisaukko-oja, S.K.; Kiuru, M.; Lehtonen, H.J.; Lehtonen, R.; Pukkala, E.; Arola, J.; Launonen, V.; Aaltonen, L.A.
Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients
Int. J. Cancer
119
283-287
2006
Homo sapiens
Manually annotated by BRENDA team
Carvajal-Carmona, L.G.; Alam, N.A.; Pollard, P.J.; Jones, A.M.; Barclay, E.; Wortham, N.; Pignatelli, M.; Freeman, A.; Pomplun, S.; Ellis, I.; Poulsom, R.; El-Bahrawy, M.A.; Berney, D.M.; Tomlinson, I.P.
Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations
J. Clin. Endocrinol. Metab.
91
3071-3075
2006
Homo sapiens
Manually annotated by BRENDA team
Pithukpakorn, M.; Wei, M.H.; Toure, O.; Steinbach, P.J.; Glenn, G.M.; Zbar, B.; Linehan, W.M.; Toro, J.R.
Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer
J. Med. Genet.
43
755-762
2006
Homo sapiens
Manually annotated by BRENDA team
King, A.; Selak, M.A.; Gottlieb, E.
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
Oncogene
25
4675-4682
2006
Homo sapiens
Manually annotated by BRENDA team
Raimundo, N.; Ahtinen, J.; Fumic, K.; Baric, I.; Remes, A.M.; Renkonen, R.; Lapatto, R.; Suomalainen, A.
Differential metabolic consequences of fumarate hydratase and respiratory chain defects
Biochim. Biophys. Acta
1782
287-294
2008
Homo sapiens
Manually annotated by BRENDA team
Bayley, J.; Launonen, V.; Tomlinson, I.P.
The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency
BMC Med. Genet.
9
20
2008
Homo sapiens
Manually annotated by BRENDA team
Ahvenainen, T.; Lehtonen, H.J.; Lehtonen, R.; Vahteristo, P.; Aittomaeki, K.; Baynam, G.; Dommering, C.; Eng, C.; Gruber, S.B.; Groenberg, H.; Harvima, R.; Herva, R.; Hietala, M.; Kujala, M.; Kaeaeriaeinen, H.; Sunde, L.; Vierimaa, O.; Pollard, P.J.; Tomlinson, I.P.; Bjoerck, E.; Aaltonen, L.A.; Launonen, V.
Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer
Cancer genet. Cytogenet.
183
83-88
2008
Homo sapiens
Manually annotated by BRENDA team
Lorenzato, A.; Olivero, M.; Perro, M.; Briere, J.J.; Rustin, P.; Di Renzo, M.F.
A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein
Int. J. Cancer
122
947-951
2008
Homo sapiens
Manually annotated by BRENDA team
Badeloe, S.; Bladergroen, R.S.; Jonkman, M.F.; Burrows, N.P.; Steijlen, P.M.; Poblete-Gutierrez, P.; van Steensel, M.A.; van Geel, M.; Frank, J.
Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene
J. Dermatol. Sci.
51
139-143
2008
Homo sapiens
Manually annotated by BRENDA team
Yogev, O.; Yogev, O.; Singer, E.; Shaulian, E.; Goldberg, M.; Fox, T.D.; Pines, O.
Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response
PLoS Biol.
8
e1000328
2010
Saccharomyces cerevisiae, Homo sapiens
Manually annotated by BRENDA team
Adam, J.; Yang, M.; Bauerschmidt, C.; Kitagawa, M.; OFlaherty, L.; Maheswaran, P.; Oezkan, G.; Sahgal, N.; Baban, D.; Kato, K.; Saito, K.; Iino, K.; Igarashi, K.; Stratford, M.; Pugh, C.; Tennant, D.A.; Ludwig, C.; Davies, B.; Ratcliffe, P.J.; El-Bahrawy, M.; Ashrafian, H.; Soga, T.; Pollard, P.J.
A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
Cell Rep.
3
1440-1448
2013
Homo sapiens
Manually annotated by BRENDA team
Pereira De Padua, R.; Nonato, M.
Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of recombinant human fumarase
Acta Crystallogr. Sect. F
70
120-122
2014
Homo sapiens (P07954), Homo sapiens
Manually annotated by BRENDA team
Bulku, A.; Weaver, T.M.; Berkmen, M.B.
Biochemical characterization of two clinically-relevant human fumarase variants defective for oligomerization
Open Biochem. J.
12
1-15
2018
Homo sapiens (P07954), Homo sapiens
Manually annotated by BRENDA team