FH

Official Full Name

fumarate hydratase

Organism

Homo sapiens

GeneID

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;

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

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.

Fig1 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:

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.
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.
Jr, W. (2005). 'The von hippel-lindau protein, hif hydroxylation, and oxygen sensing.' Biochemical & Biophysical Research Communications, 338(1), 627-638.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry