FH
The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]
Full Name
Fumarate Hydratase
Function
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).
Isoform Mitochondrial:
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.
Isoform Cytoplasmic:
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).
Biological Process
Cellular response to DNA damage stimulus Source: UniProtKB
DNA repair Source: UniProtKB-KW
Fumarate metabolic process Source: UniProtKB
Homeostasis of number of cells within a tissue Source: Ensembl
Malate metabolic process Source: UniProtKB
Negative regulation of histone H3-K36 methylation Source: UniProtKB
Positive regulation of cold-induced thermogenesis Source: YuBioLab
Positive regulation of double-strand break repair via nonhomologous end joining Source: UniProtKB
Regulation of arginine metabolic process Source: UniProtKB
Tricarboxylic acid cycle Source: GO_Central
Urea cycle Source: UniProtKB
Cellular Location
Isoform Mitochondrial: Mitochondrion
Isoform Cytoplasmic: Cytosol; Nucleus; Chromosome. Translocates to the nucleus in response to DNA damage: localizes to DNA double-strand breaks (DSBs) following phosphorylation by PRKDC.
Involvement in disease
Fumarase deficiency (FMRD):
A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy.
Hereditary leiomyomatosis and renal cell cancer (HLRCC):
Isoform Cytoplasmic:
The disease is caused by variants affecting the gene represented in this entry. Isoform Cytoplasmic: HLRCC is probably caused by an accumulation of fumarate (PubMed:30718813). Accumulation of fumarate coupled with protonation promotes the formation of non-enzymatic post-translational modification cysteine S-succination (S-(2-succinyl)cysteine) on proteins, such as SMARCC1 (PubMed:30718813). A disorder characterized by predisposition to cutaneous and uterine leiomyomas, and papillary type 2 renal cancer which occurs in about 20% of patients.
PTM
Isoform Cytoplasmic:
Phosphorylation at Thr-236 by PRKDC in response to DNA damage promotes translocation to the nucleus and recruitment to DNA double-strand breaks (DSBs).
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