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FH


Official Full Name
fumarate hydratase
Organism
Homo sapiens
Gene ID
2271
Background
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]
Synonyms
MCL; FMRD; HsFH; LRCC; HLRCC; MCUL1

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SHG169093 shRNA set against Rat Cfh(NM_130409.2) Inquiry
SHH145533 shRNA set against Rat Ldlr(NM_175762.2) Inquiry
SHH329344 shRNA set against Rat LDLR (NM_175762.2) Inquiry
SHG169297 shRNA set against Mouse Cfh(NM_009888.3) Inquiry
SHH262417 shRNA set against Human Cfh (NM_000186.3) Inquiry
SHH262421 shRNA set against Mouse Cfh (NM_009888.3) Inquiry
SHH294801 shRNA set against Mouse FH (NM_175276.3) Inquiry
SHH329335 shRNA set against Human LDLR (NM_000527.4) Inquiry
SHH329339 shRNA set against Mouse LDLR (NM_010700.3) Inquiry
SHW000466 shRNA set against Chicken FH (NM_001006382) Inquiry
SHW004965 shRNA set against Chicken LDLR (NM_204452) Inquiry
SHW013733 shRNA set against Danio rerio CFH (NM_001199190) Inquiry
SHW017084 shRNA set against Danio rerio FH (NM_200963) Inquiry
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SKO0479 FH Validated sgRNA vector Inquiry
CDCL151278 Mouse Ldlr ORF clone (NM_001252659.1) Inquiry
CDFL002638 Mouse Cfh cDNA Clone(NM_009888.3) Inquiry
CDFR011075 Rat Fh cDNA Clone(NM_017005.2) Inquiry
CDFR013884 Rat Cfh cDNA Clone(NM_130409.2) Inquiry
CDFR014870 Rat Ldlr cDNA Clone(NM_175762.2) Inquiry
MiUTR3H-08845 LDLR miRNA 3'UTR clone Inquiry
MiUTR1M-02968 CFH miRNA 3'UTR clone Inquiry
CDCL126663 Human LDLR ORF clone (NM_001195799.1) Inquiry
MiUTR1R-01907 FH miRNA 3'UTR clone Inquiry
MiUTR1R-02978 LDLR miRNA 3'UTR clone Inquiry
CDCB178559 Danio rerio FH ORF Clone (NM_200963) Inquiry
MiUTR3H-00770 CFH miRNA 3'UTR clone Inquiry
MiUTR3H-00771 CFH miRNA 3'UTR clone Inquiry
CDCB161941 Chicken FH ORF Clone (NM_001006382) Inquiry
MiUTR3H-00833 FH miRNA 3'UTR clone Inquiry
MiUTR1R-00949 CFH miRNA 3'UTR clone Inquiry
CDCS405486 Human CFH ORF Clone (BC037285) Inquiry
CDCS405453 Human FH ORF Clone (BC003108) Inquiry
CDCR381787 Rat Ldlr ORF Clone(NM_175762.2) Inquiry
CDCR380918 Rat Cfh ORF Clone(NM_130409.2) Inquiry
CDCR046344 Human CFH ORF clone (NM_001014975.2) Inquiry
CDCR046346 Mouse Cfh ORF clone (NM_009888.3) Inquiry
CDCB157200 Mouse LDLR ORF clone (NM_010700.2) Inquiry
CDCB166440 Chicken LDLR ORF Clone (NM_204452) Inquiry
CDCB175208 Danio rerio CFH ORF Clone (NM_001199190) Inquiry
CDCB180785 Rabbit LDLR ORF clone (NM_001278865.1) Inquiry
CDCB181791 Rabbit C3H5orf46 ORF clone (XM_008255203.1) Inquiry
CDCB183347 Rabbit FH ORF clone (XM_002717334.2) Inquiry
CDCR378118 Rat Fh ORF Clone(NM_017005.2) Inquiry
CDCB193526 Rabbit CFH ORF clone (XM_008268719.1) Inquiry
CDCL126667 Mouse LDLR ORF clone (NM_001195798.1) Inquiry
CDCL126669 Mouse LDLR ORF clone (NM_001195800.1) Inquiry
CDCL126671 Human LDLR ORF clone (NM_001195802.1) Inquiry
CDCL151276 Mouse Ldlr ORF clone (NM_001252658.1) Inquiry
CDCL183534 Human CFH ORF clone(NM_000186.3) Inquiry
CDCL184279 Human FH ORF clone(NM_000143.3) Inquiry
CDCL126665 Human LDLR ORF clone (NM_001195803.1) Inquiry
CDCB156200 Rat CFH ORF clone (BC089845.1) Inquiry

Detailed Information

Fumarate hydratase (FH) catalyzes the reversible hydration reaction of fumarate to L-malic acid, which is widely present in animals, plants and microorganisms. FH is expressed in both mitochondria and cytoplasm. While participating in the tricarboxylic acid cycle (TCA) in the mitochondria, it also participates in the metabolism of fumaric acid in the cytoplasm to regulate fumaric acid levels. Loss of FH gene will cause many human diseases. For example, fumarate hydratase deficiency is an autosomal recessive genetic disease, manifested as metabolic disorders, severe encephalopathy, seizures and poor neurological prognosis. A large number of studies have shown that gene mutations of enzymes involved in the tricarboxylic acid cycle may cause the occurrence and development of tumors.

The Structure of Fumarate Hydratase

Fumarate hydratase is an enzyme in the tricarboxylic acid cycle, which mainly catalyzes the hydration of fumarate to form L-malic acid. The catalytic reaction of the enzyme is reversible, but has strict stereoselectivity. The hydroxyl group that cleaves is strictly added to one side of the double bond of the fumaric acid molecule, and hydrogen is added to the other side. Therefore, in the reaction, it only catalyzes the hydration of the trans-double-shoulder (fumaric acid), but not maleic acid. The reverse reaction only catalyzes the formation of the L-isomer of silicic acid. Fumarate hydratase belongs to a family of homologous enzymes containing similar amino acid sequences. It is a key enzyme involved in energy metabolism.

Fumarate Hydrate and Tumor

Multiple skin and uterine leiomyoma syndrome (MCUL) is an autosomal dominant hereditary tumor susceptibility disease, which mainly occurs in the skin and uterine smooth muscle. When associated with renal cell carcinoma, this syndrome is called hereditary leiomyoma and renal cell carcinoma (HLRCC). Mutations in FH cause hereditary skin leiomyomas and have specific correlations. Studies on families with HLRCC found that approximately one-third of patients have kidney cancer. Studies have shown that when the fumarate hydratase gene is lacking, fumarate accumulates, which activates an abnormal physiological pathway in uterine muscle cells, thereby causing uterine fibroids.

False hypoxia-driven mechanism of HLRCCFig1 False hypoxia-driven mechanism of HLRCC

Pathogenic Mechanism of Fumarate Hydratase

The pathogenic mechanism of HLRCC is related to pseudo-hypoxic drive. Pseudo-hypoxic drive refers to the activation of hypoxia signaling pathways under conditions of re-hypoxia. Studies have confirmed that the expression levels of HIF-1α and HIF-2α in HLRCC tumor cells are significantly increased. HIF is a key regulator for regulating oxygen balance. Strict regulation of HIF under hypoxic conditions can ensure the survival and growth of cells. HIF regulates vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), vascular endothelial growth factor receptor (EGFR), glucose transporter 1 Glucose Transporter Protein (GTP1), crude erythropoietin, transforming growth factor-α. Fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate-dependent dioxygenases, such as histone demethylase, prolyl hydroxylase, and collagen prolyl 4- Hydroxylase and 5-methylcytosine hydroxylase family. The Von Hippel-Lindau (VHL) complex can specifically bind to HIF-1α and HIF-2α and degrade them. However, the VHL complex can only recognize HIF where the proline residue is hydroxylated. Hydroxylation of the proline residues of HIF requires the participation of prolyl hydroxylase, oxygen molecules and α-ketoglutarate. Under hypoxic conditions, HIF makes it non-hydroxylated, so it can avoid binding to VHL complexes. The accumulation of HIF leads to an increase in downstream glycolysis, a decrease in the mitochondrial respiratory chain and a hierarchical mitochondrial autophagy to avoid normal energy metabolism pathways, which in turn causes the occurrence of tumors.

References:

  1. Tuboi, S. , Suzuki, T. , Sato, M. , & Yoshida, T. (1990). 'Rat liver mitochondrial and cytosolic fumarases with identical amino acid sequences are encoded from a single mrna with two alternative in-phase aug initiation sites'. Advances in Enzyme Regulation, 30, 289-294.
  2. Zinn, A. B. , Kerr, D. S. , & Hoppel, C. L. (1986). 'Fumarase deficiency: a new cause of mitochondrial encephalomyopathy.' New England Journal of Medicine, 315(8), 469-75.
  3. Jr, W. (2005). 'The von hippel-lindau protein, hif hydroxylation, and oxygen sensing.' Biochemical & Biophysical Research Communications, 338(1), 627-638.
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