Fumarate hydratase, mitochondrial (FH)
The protein contains 510 amino acids for an estimated molecular weight of 54637 Da.
Catalyzes the reversible stereospecific interconversion of fumarate to L-malate (PubMed:30761759). Experiments in other species have demonstrated that specific isoforms of this protein act in defined pathways and favor one direction over the other (Probable).', 'Catalyzes the hydration of fumarate to L-malate in the tricarboxylic acid (TCA) cycle to facilitate a transition step in the production of energy in the form of NADH.', "Catalyzes the dehydration of L-malate to fumarate (By similarity). Fumarate metabolism in the cytosol plays a role during urea cycle and arginine metabolism; fumarate being a by-product of the urea cycle and amino-acid catabolism (By similarity). Also plays a role in DNA repair by promoting non-homologous end-joining (NHEJ) (PubMed:20231875, PubMed:26237645). In response to DNA damage and phosphorylation by PRKDC, translocates to the nucleus and accumulates at DNA double-strand breaks (DSBs): acts by catalyzing formation of fumarate, an inhibitor of KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 'Lys-36' (H3K36me2) (PubMed:26237645). (updated: Dec. 11, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
Biological Process
Cellular metabolic process
Cellular response to DNA damage stimulus
DNA repair
Fumarate metabolic process
Homeostasis of number of cells within a tissue
Malate metabolic process
Negative regulation of histone H3-K36 methylation
Positive regulation of cold-induced thermogenesis
Positive regulation of double-strand break repair via nonhomologous end joining
Regulation of arginine metabolic process
Small molecule metabolic process
Tricarboxylic acid cycle
Urea cycle
The reference OMIM entry for this protein is 136850
Fumarate hydratase; fh
Fumarase fumarate hydratase, cytosolic, included; fh1, included
Fumarate hydratase, mitochondrial, included; fh2, included
DESCRIPTION
Fumarate hydratase, or fumarase (EC 4.2.1.2), is an enzymatic component of the tricarboxylic acid, or Krebs, cycle. It catalyzes the conversion of fumarate to malate.CLONING
Edwards and Hopkinson (1979) studied a family with an electrophoretic variant of FH. Two persons had variation in both the soluble and the mitochondrial forms, suggesting that they are determined by a single locus. Doonan et al. (1984) cited evidence suggesting that the isoenzymes of fumarase are translated in precursor form from 2 different mRNA molecules, these mRNAs in turn arising from alternative splicing of a single gene transcript. Using peptide mapping, O'Hare and Doonan (1985) showed that the cytosolic and mitochondrial fumarases from pig liver are identical over nearly all of their amino acid sequences, but that they differ at their N termini. Kinsella and Doonan (1986) cloned human fumarase from a liver cDNA library. The deduced 468-amino acid protein, with the exception of an N-terminal methionine, appeared to be the mitochondrial form. Kinsella and Doonan (1986) found an unusually high degree of identity of structure between human fumarase and that from B. subtilis and E. coli. Suzuki et al. (1989) cloned rat liver fumarase, which encodes a deduced 507-amino acid protein with a 41-amino acid prosequence. Comparison of mature peptide sequences of mitochondrial and cytosolic fumarases revealed identity, with the exception that the N-terminal alanine of cytosolic fumarase was acetylated. Northern blot analysis of rat liver showed a single mRNA species of about 1.8 kb. Suzuki et al. (1989) concluded that the mitochondrial and cytosolic forms of fumarase are encoded by a single transcript and that posttranslational processing directs its cellular localization. By immunohistochemical analysis, Bourgeron et al. (1994) found that fumarase localized to the mitochondrion, but not cytosol, in normal human brain, consistent with the findings in rat.MAPPING
Van Someren et al. (1974) and Craig et al. (1976) found that the fumarase locus is on chromosome 1, possibly in the area 1q42. Despoisses et al. (1984) narrowed the regional assignment of FH to 1q42.1 by gene dosage studies in patients with various types of partial trisomy or partial monosomy of 1q. Coughlin et al. (1993) mapped the FH gene to chromosome 1 using PCR-amplified cDNA as a probe in Southern blots of genomic DNA from a series of mouse/human somatic cell hybrids. They observed related sequences on chromosomes 13 and 5.GENE FUNCTION
Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase and succinate dehydrogenases (see, e.g., SDHB 185470) act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer and to paragangliomas (see 115310), respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paragangliomas and leiomyoma and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300). Using Fh ... More on the omim web site
Jan. 22, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 27, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 12, 2019: Protein entry updated
Automatic update: model status changed
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
Oct. 27, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 136850 was added.
Feb. 25, 2016: Protein entry updated
Automatic update: model status changed
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed