Summary: Fumarate hydratase (Fumerase)
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Fumarase Edit Wikipedia article
|, fumarate hydratase, HLRCC, LRCC, MCL, MCUL1, FMRD, Fumarate hydratase, HsFH|
Fumarase (or fumarate hydratase) is an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs Cycle (also known as the Tricarboxylic Acid Cycle [TCA] or the Citric Acid Cycle), and the cytosolic isoenzyme is involved in the metabolism of amino acids and fumarate. Subcellular localization is established by the presence of a signal sequence on the amino terminus in the mitochondrial form, while subcellular localization in the cytosolic form is established by the absence of the signal sequence found in the mitochondrial variety.
This enzyme participates in 2 metabolic pathways: citric acid cycle, reductive citric acid cycle (CO2 fixation), and is also important in renal cell carcinoma. Mutations in this gene have been associated with the development of leiomyomas in the skin and uterus in combination with renal cell carcinoma.
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is (S)-malate hydro-lyase (fumarate-forming). Other names in common use include:
- L-malate hydro-lyase
- (S)-malate hydro-lyase
The FH gene is localized to the chromosomal position 1q42.3-q43. The FH gene contains 10 exons.
Crystal structures of fumarase C from Escherichia coli have been observed to have two occupied dicarboxylate binding sites. These are known as the active site and the B site. The active site and B site are both identified as having areas unoccupied by a bound ligand. This so-called â€˜freeâ€™ crystal structure demonstrates conservation of the active-site water. Similar orientation has been discovered in other fumarase C crystal structures. Crystallographic research on the B site of the enzyme has observed that there is a shift on His129. This information suggests that water is a permanent component of the active site. It also suggests that the use of an imidazole-imidazolium conversion controls access to the allosteric B site.
Figure 2 depicts the fumarase reaction mechanism. Two acid-base groups catalyze proton transfer, and the ionization state of these groups is in part defined by two forms of the enzyme E1 and E2. In E1, the groups exist in an internally neutralized A-H/B: state, while in E2, they occur in a zwitterionic A-/BH+ state. E1 binds fumarate and facilitates its transformation into malate, and E2 binds malate and facilitates its transformation into fumarate. The two forms must undergo isomerization with each catalytic turnover.
Despite its biological significance, the reaction mechanism of fumarase is not completely understood. The reaction itself can be monitored in either direction; however, it is the formation of fumarate from S-malate in particular that is less understood due to the high pKa value of the HR (Fig. 1) atom that is removed without the aid of any cofactors or coenzymes. However, the reaction from fumarate to L-malate is better understood, and involves a stereospecific hydration of fumarate to produce S-malate by trans-addition of a hydroxyl group and a hydrogen atom through a trans 1,4 addition of a hydroxyl group. Early research into this reaction suggested that the formation of fumarate from S-malate involved dehydration of malate to a carbocationic intermediate, which then loses the alpha proton to form fumarate. This led to the conclusion that in the formation of S-Malate from fumarate E1 elimination, protonation of fumarate to the carbocation was followed by the additional of a hydroxyl group from H2O. However, more recent trials have provided evidence that the mechanism actually takes place through an acid-base catalyzed elimination by means of a carbanionic intermediate E1CB elimination (Figure 2).
The function of fumarase in the citric acid cycle is to facilitate a transition step in the production of energy in the form of NADH. In the cytosol the enzyme functions to metabolize fumarate, which is a byproduct of the urea cycle as well as amino acid catabolism. Studies have revealed that the active site is composed of amino acid residues from three of the four subunits within the tetrameric enzyme.
The primary binding site on fumarase is known as catalytic site A. Studies have revealed that catalytic site A is composed of amino acid residues from three of the four subunits within the tetrameric enzyme. Two potential acid-base catalytic residues in the reaction include His 188 and Lys 324.
There are two classes of fumarases. Classifications depend on the arrangement of their relative subunit, their metal requirement, and their thermal stability. These include class I and class II. Class I fumarases are able to change state or become inactive when subjected to heat or radiation, are sensitive to superoxide anion, are Iron II (Fe2+) dependent, and are dimeric proteins consisting of around 120 kD. Class II fumarases, found in prokaryotes as well as in eukaryotes, are tetrameric enzymes of 200,000 D that contain three distinct segments of significantly homologous amino acids. They are also iron-independent and thermal-stable. Prokaryotes are known to have three different forms of fumarase: Fumarase A, Fumarase B, and Fumarase C. Fumarase C is a part of the class II fumarases, whereas Fumarase A and Fumarase B from Escherichia coli (E. coli) are classified as class I.
Fumarase deficiency is characterized by polyhydramnios and fetal brain abnormalities. In the newborn period, findings include severe neurologic abnormalities, poor feeding, failure to thrive, and hypotonia. Fumarase deficiency is suspected in infants with multiple severe neurologic abnormalities in the absence of an acute metabolic crisis. Inactivity of both cytosolic and mitochondrial forms of fumarase are potential causes. Isolated, increased concentration of fumaric acid on urine organic acid analysis is highly suggestive of fumarase deficiency. Molecular genetic testing for fumarase deficiency is currently available.
Fumarase is prevalent in both fetal and adult tissues. A large percentage of the enzyme is expressed in the skin, parathyroid, lymph, and colon. Mutations in the production and development of fumarase have led to the discovery of several fumarase-related diseases in humans. These include benign mesenchymal tumors of the uterus, leiomyomatosis and renal cell carcinoma, and fumarase deficiency. Germinal mutations in fumarase are associated with two distinct conditions. If the enzyme has missense mutation and in-frame deletions from the 3â€™ end, fumarase deficiency results. If it contains heterozygous 5â€™ missense mutation and deletions (ranging from one base pair to the whole gene), then leiomyomatosis and renal cell carcinoma/Reedâ€™s syndrome (multiple cutaneous and uterine leiomyomatosis) could result.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [Â§ 1]
- GRCh38: Ensembl release 89: ENSG00000091483 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000026526 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- FH (fumarate hydratase)
- Weaver T (October 2005). "Structure of free fumarase C from Escherichia coli". Acta Crystallogr. D. 61 (Pt 10): 1395â€“401. doi:10.1107/S0907444905024194. PMID 16204892.
- Hegemony AD, Frey PA (2007). Enzymatic reaction mechanisms. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-512258-9.
- Begley TP, McMurry J (2005). The organic chemistry of biological pathways. Roberts and Co. Publishers. ISBN 978-0-9747077-1-6.
- Walsh C (1979). Enzymatic reaction mechanisms. San Francisco: W. H. Freeman. ISBN 978-0-7167-0070-8.
- Yogev O, Naamati A, Pines O (2011). "Fumarase: a paradigm of dual targeting and dual localized functions". The FEBS Journal. 278 (22): 4230â€“42. doi:10.1111/j.1742-4658.2011.08359.x. PMID 21929734.
- EstÃ©vez M, Skarda J, Spencer J, Banaszak L, Weaver TM (June 2002). "X-ray crystallographic and kinetic correlation of a clinically observed human fumarase mutation". Protein Sci. 11 (6): 1552â€“7. doi:10.1110/ps.0201502. PMC 2373640. PMID 12021453.[permanent dead link]
- Lynch AM, Morton CC (2006-07-01). "FH (fumarate hydratase)". Atlas of Genetics and Cytogenetics in Oncology and Haematology.
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Fumarate hydratase (Fumerase) Provide feedback
This family consists of several bacterial fumarate hydratase proteins FumA and FumB. Fumarase, or fumarate hydratase (EC 220.127.116.11), is a component of the citric acid cycle. In facultative anaerobes such as Escherichia coli, fumarase also engages in the reductive pathway from oxaloacetate to succinate during anaerobic growth. Three fumarases, FumA, FumB, and FumC, have been reported in E. coli. fumA and fumB genes are homologous and encode products of identical sizes which form thermolabile dimers of Mr 120,000. FumA and FumB are class I enzymes and are members of the iron-dependent hydrolases, which include aconitase and malate hydratase. The active FumA contains a 4Fe-4S centre, and it can be inactivated upon oxidation to give a 3Fe-4S centre .
Tseng CP, Yu CC, Lin HH, Chang CY, Kuo JT; , J Bacteriol 2001;183:461-467.: Oxygen- and growth rate-dependent regulation of Escherichia coli fumarase (FumA, FumB, and FumC) activity. PUBMED:11133938 EPMC:11133938
This tab holds annotation information from the InterPro database.
InterPro entry IPR004646
This entry represents various Fe-S type hydro-lyases, including the alpha subunit from both L-tartrate dehydratase (TtdA; EC ) and class 1 fumarate hydratases ( EC ), which includes both aerobic (FumA) and anaerobic (FumB) types [ PUBMED:8371115 ]. A number of Fe-S cluster-containing hydro-lyases share a conserved motif, including argininosuccinate lyase, adenylosuccinate lyase, aspartase, class I fumarate hydratase (fumarase), and tartrate dehydratase (see INTERPRO ). Proteins in this group represent a subset of closely related proteins or modules, including the Escherichia coli tartrate dehydratase alpha chain and the N-terminal region of the class I fumarase (where the C-terminal region is homologous to the tartrate dehydratase beta chain). The activity of archaeal proteins in this group is unknown.
Fumarate hydratase (also known as fumarase) is a component of the citric acid cycle. In facultative anaerobes such as E. coli, fumarase also engages in the reductive pathway from oxaloacetate to succinate during anaerobic growth. Three fumarases, FumA, FumB, and FumC, have been reported in E. coli. fumA and fumB genes are homologous and encode products of identical sizes which form thermolabile dimers of Mr 120,000. FumA and FumB are class I enzymes and are members of the iron-dependent hydrolases, which include aconitase and malate hydratase. The active FumA contains a 4Fe-4S centre, and it can be inactivated upon oxidation to give a 3Fe-4S centre [ PUBMED:11133938 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||lyase activity (GO:0016829)|
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|Seed source:||Pfam-B_2085 (release 8.0)|
|Number in seed:||348|
|Number in full:||4945|
|Average length of the domain:||272.70 aa|
|Average identity of full alignment:||38 %|
|Average coverage of the sequence by the domain:||60.36 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||16|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Fumerase domain has been found. There are 40 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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