Gosset 5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase Overview
5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase is an enzyme encoded by the ATIC gene that catalyzes the final two steps in de novo purine biosynthesis—the conversion of AICAR (aminoimidazole carboxamide ribonucleotide) into FAICAR (formyl-AICAR) via its formyltransferase activity and then into inosine monophosphate (IMP) via its IMP cyclohydrolase activity. This bifunctional enzyme is essential for nucleotide production required for DNA/RNA synthesis. It is a key target for antifolate drugs such as methotrexate; inhibition leads to reduced purine synthesis and accumulation of AICAR derivatives that increase extracellular adenosine—a potent anti-inflammatory mediator—explaining part of methotrexate’s therapeutic effect in autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease. Mutations can cause rare metabolic disorders such as AICA-ribosiduria with neurological symptoms. The protein exists mainly as a dimer when active but can exist in equilibrium between monomeric and dimeric forms depending on substrate presence.
Mechanism of Action
Inhibition by methotrexate polyglutamates, leading to blockade of purine synthesis and increased adenosine accumulation, which has anti-inflammatory effects
Biological Functions
Disease Associations
Safety Considerations
- Notable safety concerns relate primarily to drugs targeting this enzyme, such as methotrexate toxicity—manifesting as myelosuppression, hepatotoxicity, mucositis, and increased risk of infection due to impaired nucleotide synthesis. Genetic polymorphisms in the ATIC gene may also influence drug response or adverse effects.
Interacting Drugs
Associated Biomarkers
| Biomarker |
|---|
| Methotrexate polyglutamate levels in cells are used as a biomarker for efficacy and toxicity monitoring in diseases like rheumatoid arthritis and inflammatory bowel disease, reflecting inhibition of ATIC activity. |