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Gene Review

Fh1  -  fumarate hydratase 1

Mus musculus

Synonyms: EF-3, Fh, Fh-1, Fumarase, Fumarate hydratase, mitochondrial, ...
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Disease relevance of Fh1


High impact information on Fh1

  • By comparing the scrambling of 13C between C3 and C2 of glutamate it is possible to estimate the mitochondrial fumarase activity; the C6-to-C5 ratios in glucose give the additional scrambling by cytosolic fumarase activity [5].
  • We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell [1].
  • In the present study, the spatial distribution of hypoxia during PDT was quantified using the hypoxia-labeling marker EF3 [2].
  • Cryosectioning, immunohistochemistry, and fluorescence microscopy were carried out to quantify EF3 binding as a function of distance to the nearest perfused blood vessels in sections cut from within the superficial (light-adjacent) 600 micro m or the deep (light-distant) 600 micro m of tumors (5-6 mm in diameter, approximately 3 mm in depth) [2].
  • Here we present structural and binding studies on single-site mutants of DREAM designed to disable Ca(2+) binding to each of the functional EF-hands (EF-2: D150N; EF-3: E186Q; and EF-4: E234Q) [6].

Biological context of Fh1

  • None of the EF-hand mutants bind DRE at saturating Ca(2+) levels, suggesting that binding of a single Ca(2+) at either EF-3 or EF-4 is sufficient to drive conformational changes that abolish DNA binding [6].
  • A mutant in the fumarase gene demonstrated reduced virulence for mice and an inability to grow in cultured mouse phagocytes [7].

Anatomical context of Fh1

  • The relative specific activity of PDHC in cytoplasmic or synaptoplasmic fractions was less than that of two other mitochondrial enzymes, fumarase (EC and monoamine oxidase (EC, which argues strongly against the hypothesis of a cytoplasmic PDHC in cholinergic nerve endings [8].
  • Administration of MPTP in mice resulted in inactivation of mitochondrial aconitase, but not fumarase in the substantia nigra [9].
  • Two putative precursor polypeptides of rat liver fumarase were synthesized when rat liver RNA was translated in vitro in a rabbit reticulocyte lysate system.(ABSTRACT TRUNCATED AT 400 WORDS)[10]
  • The investigation of the intracellular distribution of hepatic fumarase of the rat, mouse, rabbit, dog, chicken, snake, frog, and carp revealed that the amount of the enzyme located in the cytosol was comparable to that in the mitochondria of all these animals [11].
  • The amount of fumarase associated with the microsomes was less than 5% of the total enzyme activity [11].

Associations of Fh1 with chemical compounds

  • Isothermal titration calorimetry (ITC) analysis of Ca(2+) binding to the various mutants revealed that, in the absence of Mg(2+), Ca(2+) binds independently and sequentially to EF-3 (DeltaH = -2.4 kcal/mol), EF-4 (DeltaH = +5.2 kcal/mol), and EF-2 (DeltaH = +1 kcal/mol) [6].
  • Nine in vivo induced loci were identified including genes encoding a DNA topoisomerase III, a cellobiose transporter and a fumarase [7].
  • The activities of mitochondrial malic enzyme, fumarase, and lactate dehydrogenase were high enough to account for the formation of [2-13C]lactate in neurons [12].
  • A rapid three-step procedure utilizing heat treatment, ammonium sulfate fractionation, and affinity chromatography on Matrex gel Orange A purified fumarase (EC 632-fold with an 18% yield from crude extracts of Euglena gracilis var. bacillaris [13].
  • Two bands each of triose phsophate isomerase, fumarase and aldolase are present in brain, but only one band of these enzymes is present in neuroblastoma cells [14].

Other interactions of Fh1

  • In contrast, levels of enkephalin convertase activity, cell protein, lactate dehydrogenase, fumarase, and lysosomal carboxypeptidase did not decline in response to chronic glucocorticoid exposure [15].
  • In CR mice, the cycle was divided into two major blocks, the first containing citrate synthase, aconitase and NAD-dependent isocitrate dehydrogenase which showed decreased activities, while the second block, containing the remaining enzymes, displayed increased activity (except for fumarase, which was unchanged) [16].
  • Echinococcus granulosus cyst wall exhibited activities of fumarate hydratase (FH), pyruvate kinase (PK), and phosphoenolpyruvate carboxykinase (PEPCK) with 911-1433, 151-215, and 54-98U, respectively [17].

Analytical, diagnostic and therapeutic context of Fh1

  • Depletion of tumor oxygenation during photodynamic therapy: detection by the hypoxia marker EF3 [2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl)acetamide ] [3].


  1. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Alam, N.A., Rowan, A.J., Wortham, N.C., Pollard, P.J., Mitchell, M., Tyrer, J.P., Barclay, E., Calonje, E., Manek, S., Adams, S.J., Bowers, P.W., Burrows, N.P., Charles-Holmes, R., Cook, L.J., Daly, B.M., Ford, G.P., Fuller, L.C., Hadfield-Jones, S.E., Hardwick, N., Highet, A.S., Keefe, M., MacDonald-Hull, S.P., Potts, E.D., Crone, M., Wilkinson, S., Camacho-Martinez, F., Jablonska, S., Ratnavel, R., MacDonald, A., Mann, R.J., Grice, K., Guillet, G., Lewis-Jones, M.S., McGrath, H., Seukeran, D.C., Morrison, P.J., Fleming, S., Rahman, S., Kelsell, D., Leigh, I., Olpin, S., Tomlinson, I.P. Hum. Mol. Genet. (2003) [Pubmed]
  2. Photodynamic therapy creates fluence rate-dependent gradients in the intratumoral spatial distribution of oxygen. Busch, T.M., Wileyto, E.P., Emanuele, M.J., Del Piero, F., Marconato, L., Glatstein, E., Koch, C.J. Cancer Res. (2002) [Pubmed]
  3. Depletion of tumor oxygenation during photodynamic therapy: detection by the hypoxia marker EF3 [2-(2-nitroimidazol-1[H]-yl)-N-(3,3,3-trifluoropropyl)acetamide ]. Busch, T.M., Hahn, S.M., Evans, S.M., Koch, C.J. Cancer Res. (2000) [Pubmed]
  4. Changes induced by Ehrlich ascites carcinoma in hepatic fumarase and aconitase activities. Abreu, L.A., Abreu, R.R. Experientia (1978) [Pubmed]
  5. Effects of ethanol on alanine metabolism in perfused mouse liver studied by 13C NMR. Cohen, S.M., Shulman, R.G., McLaughlin, A.C. Proc. Natl. Acad. Sci. U.S.A. (1979) [Pubmed]
  6. Mg2+ and Ca2+ differentially regulate DNA binding and dimerization of DREAM. Osawa, M., Dace, A., Tong, K.I., Valiveti, A., Ikura, M., Ames, J.B. J. Biol. Chem. (2005) [Pubmed]
  7. The use of listeriolysin to identify in vivo induced genes in the gram-positive intracellular pathogen Listeria monocytogenes. Gahan, C.G., Hill, C. Mol. Microbiol. (2000) [Pubmed]
  8. Studies on the pyruvate dehydrogenase complex in brain with the arylamine acetyltransferase-coupled assay. Ksiezak-Reding, H., Blass, J.P., Gibson, G.E. J. Neurochem. (1982) [Pubmed]
  9. Iron-sulfur enzyme mediated mitochondrial superoxide toxicity in experimental Parkinson's disease. Liang, L.P., Patel, M. J. Neurochem. (2004) [Pubmed]
  10. Mechanism of synthesis and localization of mitochondrial and cytosolic fumarases in rat liver. Tuboi, S., Sato, M., Ono, H., Kobayashi, K., Hiraga, K. Adv. Enzyme Regul. (1986) [Pubmed]
  11. Intracellular distribution of fumarase in various animals. Akiba, T., Hiraga, K., Tuboi, S. J. Biochem. (1984) [Pubmed]
  12. Cerebral metabolism of lactate in vivo: evidence for neuronal pyruvate carboxylation. Hassel, B., Bråthe, A. J. Cereb. Blood Flow Metab. (2000) [Pubmed]
  13. Purification, characterization, and immunological properties of fumarase from Euglena gracilis var. bacillaris. Shibata, H., Gardiner, W.E., Schwartzbach, S.D. J. Bacteriol. (1985) [Pubmed]
  14. Altered enzyme expression in "differentiated" murine neuroblastoma cells. Prasad, N., Prasad, R. Br. J. Cancer (1976) [Pubmed]
  15. Secretion and regulation of two biosynthetic enzyme activities, peptidyl-glycine alpha-amidating monooxygenase and a carboxypeptidase, by mouse pituitary corticotropic tumor cells. Mains, R.E., Eipper, B.A. Endocrinology (1984) [Pubmed]
  16. Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction. Hagopian, K., Ramsey, J.J., Weindruch, R. Exp. Gerontol. (2004) [Pubmed]
  17. Effects of mebendazole, albendazole, and praziquantel on fumarate hydratase, pyruvate kinase, and phosphoenolpyruvate carboxykinase of Echinococcus granulosus cyst wall harbored in mice. Xiao, S.H., Feng, J.J., Guo, H.F., Jiao, P.Y., Yao, M.Y., Jiao, W. Zhongguo yao li xue bao = Acta pharmacologica Sinica. (1994) [Pubmed]
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