Gamma-glutamyl hydrolase

Gamma-glutamyl hydrolase (GGH) is an enzyme that plays a crucial role in the metabolism of folates, a group of water-soluble B-vitamins that are essential for the synthesis and repair of DNA and RNA in the human body. GGH catalyzes the hydrolysis of poly-γ-glutamate chains of folates to monoglutamate forms, which are necessary for folate absorption and intracellular transport. This process is vital for the maintenance of normal cellular functions, including cell division and the synthesis of nucleotides.

Function

Gamma-glutamyl hydrolase is primarily involved in the metabolism of folates, compounds that are critical for the synthesis of purines and pyrimidines, which in turn are essential components of nucleic acids. By converting polyglutamated folates to their monoglutamate forms, GGH facilitates the cellular uptake and utilization of folates. This enzymatic activity is particularly important in rapidly dividing cells, such as those found in the bone marrow and developing embryos, where the demand for DNA and RNA synthesis is high.

Structure

The structure of gamma-glutamyl hydrolase has been studied extensively to understand its function at the molecular level. GGH is a lysosomal enzyme that is encoded by the GGH gene in humans. The enzyme's structure reveals a mechanism that allows it to specifically recognize and cleave the γ-glutamyl bond in folates, distinguishing it from other enzymes that act on glutamates.

Clinical Significance

Alterations in the activity or expression of GGH can have significant clinical implications. High levels of GGH activity can lead to reduced intracellular concentrations of polyglutamated folates, potentially resulting in folate deficiency. This condition is associated with several health issues, including neural tube defects in developing embryos, Megaloblastic anemia, and increased risk of certain cancers due to impaired DNA synthesis and repair.

Conversely, low GGH activity can lead to the accumulation of polyglutamated folates within cells, which may interfere with the efficacy of certain chemotherapeutic agents, such as methotrexate, that target folate metabolism. Understanding the regulation of GGH activity and its impact on folate homeostasis is therefore of great interest in the context of both nutrition and cancer therapy.

Genetic Variability

The GGH gene exhibits genetic variability among individuals, which can affect the enzyme's activity and thus influence folate metabolism. Single nucleotide polymorphisms (SNPs) in the GGH gene have been associated with variations in enzyme activity and folate levels in the body, as well as differential responses to methotrexate treatment in patients with conditions like Rheumatoid arthritis and Leukemia.

See Also

• Folate
• Folate metabolism
• Methotrexate
• Neural tube defect
• Megaloblastic anemia