Bifunctional purine biosynthesis protein ATIC (ATIC) (ATIC)

Bifunctional purine biosynthesis protein ATIC (ATIC) is a critical metabolic enzyme that catalyzes the final two steps of the de novo purine biosynthetic pathway: the formylation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and the subsequent cyclization of the resulting intermediate into inosine monophosphate (IMP) (UniProt, https://www.uniprot.org/uniprotkb/P31939/entry). By facilitating the production of purine nucleotides, ATIC plays a fundamental role in supporting DNA and RNA synthesis, which is essential for cellular growth and proliferation (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762551/). In various malignancies, including hepatocellular carcinoma and multiple myeloma, ATIC is frequently upregulated, and its high expression levels are often associated with poor clinical outcomes and disease progression (NIH, https://pubmed.ncbi.nlm.nih.gov/39234441/). Pharmacological targeting of ATIC, particularly through antifolate inhibitors like methotrexate and pemetrexed, results in the intracellular accumulation of AICAR (also known as ZMP) (Wikipedia, https://en.wikipedia.org/wiki/ATIC). This accumulated ZMP acts as an analog of AMP, triggering the activation of the AMP-activated protein kinase (AMPK) pathway, which in turn suppresses the mTOR signaling axis and induces metabolic stress (Patsnap, https://patsnap.com/blog/aicarft-agonists-a-new-frontier-in-therapeutic-development/). Consequently, ATIC inhibition exerts potent anti-proliferative and pro-apoptotic effects, making it a valuable target for treating cancer and inflammatory conditions (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412141/). Additionally, genetic deficiency of ATIC results in AICA-ribosiduria, a rare and severe metabolic disorder characterized by neurological impairment and the excretion of AICA-riboside in urine (GeneCards, https://www.genecards.org/cgi-bin/cardprep.pl?gene=ATIC).

Other names

AICARFTIMPCHASEPURHAICAR transformylase5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolaseBifunctional purine biosynthesis protein PURH

Inhibition of the AICAR transformylase domain prevents the conversion of AICAR to FAICAR, leading to the accumulation of intracellular AICAR (ZMP). ZMP acts as an AMP mimetic that activates the AMPK pathway, which subsequently inhibits mTOR signaling and other anabolic processes. This mechanism, combined with the depletion of downstream purine nucleotides (IMP, ATP, GTP), results in the inhibition of DNA/RNA synthesis, cell cycle arrest, and apoptosis in rapidly dividing cells.