Fumarate hydratase, mitochondrial(FH)

Description of Fumarate hydratase, mitochondrial(FH)

Fumarate Hydratase, Mitochondrial (FH): A Key Drug Target for Cancer Treatment

Introduction

Fumarate hydratase, mitochondrial (FH) is a crucial enzyme involved in the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle. It is responsible for converting fumarate to malate, a key step in the production of energy in the form of ATP. FH is located in the mitochondria, the powerhouse of the cell, and plays a vital role in cellular metabolism. In recent years, FH has gained significant attention as a potential drug target for cancer treatment. In this article, we will discuss the structure, activity, and application of FH as a drug target.

Structure of FH

FH is a homotetrameric enzyme, meaning it is composed of four identical subunits. Each subunit consists of approximately 500 amino acids and has a molecular weight of 53 kDa. The overall structure of FH is similar to other fumarate hydratase enzymes found in the cytosol and the chloroplast. However, the mitochondrial FH has a unique N-terminal extension that is essential for its localization and function in the mitochondria.

The active site of FH is located in the center of the tetramer, where fumarate binds and undergoes a dehydration reaction to form malate. This reaction is facilitated by a catalytic triad of amino acids, including a histidine, an aspartate, and a serine residue. Mutations in these amino acids can lead to the loss of FH activity, resulting in a rare genetic disorder called hereditary leiomyomatosis and renal cell cancer (HLRCC).

Activity of this protein

FH plays a crucial role in cellular metabolism by converting fumarate to malate in the TCA cycle. This process generates ATP, the primary source of energy for cellular processes. Additionally, FH is involved in the regulation of cellular redox balance by controlling the levels of reactive oxygen species (ROS). FH-deficient cells have been shown to have increased levels of ROS, leading to oxidative stress and DNA damage.

FH also has non-metabolic functions that contribute to its role in cancer development. Studies have shown that FH can act as a tumor suppressor by inhibiting cell proliferation and promoting cell death. It does so by interacting with and regulating the activity of other proteins involved in cell cycle control and apoptosis.

Application of FH as a Drug Target

The dysregulation of FH has been linked to various types of cancer, including renal cell carcinoma, uterine leiomyosarcoma, and papillary thyroid cancer. In HLRCC, mutations in the FH gene lead to the loss of enzyme activity, resulting in the accumulation of fumarate and the development of tumors. This makes FH an attractive target for cancer therapy.

Several studies have focused on developing small molecule inhibitors of FH as potential anticancer agents. These inhibitors bind to the active site of FH and block its activity, leading to a decrease in ATP production and an increase in ROS levels. This, in turn, triggers cell death in cancer cells while sparing normal cells. Preclinical studies have shown promising results, and clinical trials are currently underway to evaluate the efficacy of FH inhibitors in treating HLRCC and other cancers.

In addition to its potential as a drug target, FH has also been used as a biomarker for cancer diagnosis and prognosis. The loss of FH activity has been observed in various tumors, making it a potential diagnostic marker for certain types of cancer. Furthermore, the expression levels of FH have been correlated with the aggressiveness and response to treatment in some cancers.

Conclusion

Fumarate hydratase, mitochondrial (FH) is a critical enzyme involved in cellular metabolism and redox balance. Its dysregulation has been linked to various types of cancer, making it a potential drug target for cancer treatment. The unique structure and activity of FH make it an attractive target for developing small molecule inhibitors.