Formate–tetrahydrofolate ligase

PDB 1eg7 EBI

Formate–tetrahydrofolate ligase (FTHFL) is an enzyme that plays a crucial role in the metabolism of one-carbon units. This enzyme catalyzes the ATP-dependent conversion of formate and tetrahydrofolate (THF) into 10-formyltetrahydrofolate. This reaction is an essential step in the formate metabolism and is involved in the biosynthesis of purines and the metabolism of amino acids, making it vital for DNA synthesis and repair, as well as cell growth and division.

Function

Formate–tetrahydrofolate ligase is involved in the C1 metabolism pathway, which is critical for the synthesis of nucleotides and certain amino acids. The enzyme facilitates the incorporation of formate into the folate pool, converting it into a form that can be utilized in the synthesis of purines and thymidylate, which are essential for DNA synthesis and repair. This process is particularly important in rapidly dividing cells, such as those found in the bone marrow and gastrointestinal tract.

Structure

The structure of formate–tetrahydrofolate ligase includes a domain that binds ATP and a domain that binds folate. The enzyme operates through a mechanism that involves the formation of a phosphoanhydride intermediate, allowing the transfer of the formyl group to THF. The enzyme is found in a wide range of organisms, from bacteria to humans, indicating its fundamental role in cellular metabolism.

Clinical Significance

Alterations in the activity of formate–tetrahydrofolate ligase can have significant clinical implications. Deficiencies in this enzyme can lead to disruptions in nucleotide synthesis, affecting DNA repair and cell division. This can result in a variety of health issues, including megaloblastic anemia and potentially contributing to the development of certain types of cancer. Understanding the function and regulation of this enzyme is important for the development of therapeutic strategies targeting diseases associated with folate metabolism.

Genetic Regulation

The expression of the gene encoding formate–tetrahydrofolate ligase is regulated by various genetic and environmental factors. Nutritional status, particularly levels of folate and other B vitamins, can influence the activity of this enzyme. Research into the genetic regulation of FTHFL may provide insights into the mechanisms underlying diseases related to folate metabolism and offer potential targets for therapeutic intervention.

See Also

• Tetrahydrofolate
• Metabolism
• Enzyme
• DNA synthesis
• Nucleotide
• Amino acid