• homeostasis of number of cells within a tissue • tricarboxylic acid cycle • malate metabolic process • fumarate metabolic process • positive regulation of cold-induced thermogenesis
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
2271
14194
Ensembl
ENSG00000091483
ENSMUSG00000026526
UniProt
P07954
P97807
RefSeq (mRNA)
NM_000143
NM_010209
RefSeq (protein)
NP_000134
NP_034339
Location (UCSC)
Chr 1: 241.5 – 241.52 Mb
Chr 1: 175.6 – 175.63 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
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.[5]
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.
Contents
1Nomenclature
2Structure
2.1Gene
2.2Protein
3Function
3.1Mechanism
3.2Biochemical pathway
3.3Subtypes
4Clinical significance
5Interactive pathway map
6See also
7References
8External links
Nomenclature
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:
fumarase
L-malate hydro-lyase
(S)-malate hydro-lyase
Structure
Gene
The FH gene is localized to the chromosomal position 1q42.3-q43. The FH gene contains 10 exons.
Protein
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 ‘free’ 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.[6]
Function
Mechanism
Figure 1: Conversion of fumarate to S-malate.
Figure 2: Conversion of fumarate to S-malate by fumarase through a carbanion intermediate.
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.[7]
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).[7][8][9]
Biochemical pathway
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.[10] 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.[11]
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.[7][8][9]
Subtypes
There are two classes of fumarases.[12] 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.[11]
Clinical significance
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.[12]
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 3’ end, fumarase deficiency results. If it contains heterozygous 5’ missense mutation and deletions (ranging from one base pair to the whole gene), then leiomyomatosis and renal cell carcinoma/Reed’s syndrome (multiple cutaneous and uterine leiomyomatosis) could result.[11][12]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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|{{{bSize}}}px|alt=TCA Cycle edit]]
TCA Cycle edit
^The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".
See also
Fumarase deficiency
References
^ abcGRCh38: Ensembl release 89: ENSG00000091483 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000026526 - Ensembl, May 2017
^"Human PubMed Reference:".
^"Mouse PubMed Reference:".
^FH (fumarate hydratase)
^Weaver T (October 2005). "Structure of free fumarase C from Escherichia coli". Acta Crystallogr. D. 61 (Pt 10): 1395–401. doi:10.1107/S0907444905024194. PMID 16204892.
^ abcHegemony AD, Frey PA (2007). Enzymatic reaction mechanisms. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-512258-9.
^ abBegley TP, McMurry J (2005). The organic chemistry of biological pathways. Roberts and Co. Publishers. ISBN 978-0-9747077-1-6.
^ abWalsh 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): 4230–42. doi:10.1111/j.1742-4658.2011.08359.x. PMID 21929734.
^ abcEstévez 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): 1552–7. doi:10.1110/ps.0201502. PMC 2373640. PMID 12021453.[permanent dead link]
^ abcLynch AM, Morton CC (2006-07-01). "FH (fumarate hydratase)". Atlas of Genetics and Cytogenetics in Oncology and Haematology.
External links
Fumarase at the US National Library of Medicine Medical Subject Headings (MeSH)
Structure of Fumarate
Structure of S-Malate
Link to Breakdown of Citric Acid Cycle
Video of Fumarate → (S)L-Malate
v
t
e
Metabolism: Citric acid cycle enzymes
Cycle
Citrate synthase
Aconitase
Isocitrate dehydrogenase
Oxoglutarate dehydrogenase
Succinyl CoA synthetase
Succinate dehydrogenase (SDHA)
Fumarase
Malate dehydrogenase and ETC
Anaplerotic
to acetyl-CoA
Pyruvate dehydrogenase complex (E1, E2, E3)
(regulated by Pyruvate dehydrogenase kinase and Pyruvate dehydrogenase phosphatase)
to α-ketoglutaric acid
Glutamate dehydrogenase
to succinyl-CoA
Methylmalonyl-CoA mutase
to oxaloacetate
Pyruvate carboxylase
Aspartate transaminase
Mitochondrial electron transport chain/ oxidative phosphorylation
…responsible for the conversion of fumarate to malate . This disorder must be differentiated from fumarase deficiency (MIM #606812), an autosomal recessive condition that is lethal in the neonatal period…
…are now considered to be the same disease process . The mutated gene fumarate hydratase codes for fumarase, an enzyme in the Kreb cycle. The mechanism by which fumarate hydratase acts as a tumor suppressor…
English Journal
Supplementation with plant growth promoting rhizobacteria (PGPR) alleviates cadmium toxicity in Solanum lycopersicum by modulating the expression of secondary metabolites.
Khanna K, Jamwal VL, Sharma A, Gandhi SG, Ohri P, Bhardwaj R, Al-Huqail AA, Siddiqui MH, Ali HM, Ahmad P.
Chemosphere. 2019 Sep;230()628-639.
The current study evaluated the synergistic role of Plant growth promoting rhizobacteria (PGPR), Pseudomonas aeruginosa and Burkholderia gladioli on different physiological, biochemical and molecular activities of 10-days old Solanum lycopersicum seedlings under Cd stress. Cd toxicity altered the le
Oncometabolites in cancer aggressiveness and tumour repopulation.
Dando I, Pozza ED, Ambrosini G, Torrens-Mas M, Butera G, Mullappilly N, Pacchiana R, Palmieri M, Donadelli M.
Biological reviews of the Cambridge Philosophical Society. 2019 Aug;94(4)1530-1546.
Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarat
Human blood pressure salt sensitivity is associated with changes in urinary metabolites related to fumarase (Fh) and nitric oxide (NO) metabolism, and fumarase promotes NO production through an arginine regeneration pathway. We examined the role of the fumarase-NO pathway in the development of hyper
![Structure of yeast fumarase. [ 1 ] [ 2 ]](https://1mg.info/0/h/3/0632.jpg)
