fumarate hydratase

フマル酸ヒドラターゼ

関

fumarase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/11/25 21:23:27」(JST)

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fumarate hydratase Identifiers EC number 4.2.1.2 CAS number 9032-88-6 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO Search PMC articles PubMed articles NCBI proteins Fumarate hydratase (Fumarase) Structure of yeast fumarase. Identifiers Symbol Fumarase Pfam PF05681 InterPro IPR004646 Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary Fumarate hydratase Fumarase active site Identifiers Symbol FH Entrez 2271 HUGO 3700 OMIM 136850 RefSeq NM_000143 UniProt P07954 Other data EC number 4.2.1.2 Locus Chr. 1 q42.1

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 3 metabolic pathways: citric acid cycle, reductive citric acid cycle (CO₂ fixation), and in renal cell carcinoma. Mutations in this gene have been associated with the development of leiofibromyomas in the skin and uterus in combination with renal cell carcinoma.

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

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 tansformation 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 pK_a value of the H^R (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).

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. 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.

Subtypes

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.

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.

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.

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.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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TCA Cycle edit

See also

• Fumarase deficiency

References

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

UpToDate Contents

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English Journal

• Molecular pathways in renal cell carcinoma: recent advances in genetics and molecular biology.

• Su D1, Singer EA, Srinivasan R.
• Current opinion in oncology.Curr Opin Oncol.2015 May;27(3):217-23. doi: 10.1097/CCO.0000000000000186.
• PURPOSE OF REVIEW: Advanced renal cell carcinoma (RCC) remains a largely incurable disease with a grave prognosis despite the availability of a multiplicity of systemic therapies targeted against vascular endothelial growth factor, its receptors, and the mammalian target of rapamycin. Although immun
• PMID 25811348

• Oncometabolites: Tailoring our Genes.

• Nowicki S1, Gottlieb E.
• The FEBS journal.FEBS J.2015 Apr 9. doi: 10.1111/febs.13295. [Epub ahead of print]
• Increased glucose metabolism in cancer cells has been an observed phenomenon for over ninety years, allowing maximal cell growth through faster ATP production and redistribution of carbons towards nucleotide, protein and fatty acid synthesis. Recently, metabolites have been identified which can prom
• PMID 25864878

• Improved Production of Propionic Acid in Propionibacterium jensenii via Combinational Overexpression of Glycerol Dehydrogenase and Malate Dehydrogenase from Klebsiella pneumoniae.

• Liu L1, Zhuge X1, Shin HD2, Chen RR2, Li J3, Du G4, Chen J5.
• Applied and environmental microbiology.Appl Environ Microbiol.2015 Apr 1;81(7):2256-64. doi: 10.1128/AEM.03572-14. Epub 2015 Jan 16.
• Microbial production of propionic acid (PA), an important chemical building block used as a preservative and chemical intermediate, has gained increasing attention for its environmental friendliness over traditional petrochemical processes. In previous studies, we constructed a shuttle vector as a u
• PMID 25595755

Japanese Journal

• A NADH Dehydrogenase Ubiquinone Flavoprotein is Decreased in Patients with Dilated Cardiomyopathy

• Internal Medicine 49(19), 2039-2042, 2010
• NAID 130000413493

• Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene

• Journal of dermatological science 51(2), 139-143, 2008-08-01
• NAID 10024298290

• Novel mutation in a fumalate hydratase gene of a Japanese patient with multiple cutaneous and uterine leiomyomatosis

• Journal of dermatological science 48(2), 151-153, 2007-11-01
• NAID 10024117693

Related Links

• OMIM Entry - * 136850 - FUMARATE HYDRATASE; FH

TEXT Description Fumarate hydratase, or fumarase (), is an enzymatic component of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion of ...

• FH - Genetics Home Reference

The FH gene provides instructions for making an enzyme called fumarase (also known as fumarate hydratase). Fumarase participates in an important series of reactions known as the citric acid cycle or Krebs cycle, which allows ...

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リンク元	「フマル酸ヒドラターゼ」「fumarase」
関連記事	「fumarate」「hydratase」

「フマル酸ヒドラターゼ」

　　[★]

英

[[]]

同

fumarate hydratase

関

[[]]

同

fumarate hydratase

「fumarase」

　　[★]

フマラーゼ

関

fumarate hydratase

同

fumarate hydratase

「fumarate」

　　[★]

フマル酸、フマル酸塩、フマル酸エステル

関

fumaric acid

• fumaric acid

「hydratase」

　　[★]

ヒドラターゼ、水添加酵素、加水酵素

関

hydrase