Bifunctional purine biosynthesis protein PURH (ATIC) (ATIC)

The Bifunctional purine biosynthesis protein PURH, commonly known as ATIC, is a critical cytosolic enzyme that catalyzes the final two steps of the de novo purine biosynthetic pathway (UniProt P31939) [1]. It possesses two distinct catalytic activities: 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase and inosine monophosphate (IMP) cyclohydrolase (NCBI Gene ID 471) [2]. By converting AICAR to IMP, ATIC ensures the production of essential purine nucleotides required for DNA replication and RNA transcription [1]. This enzyme is a major therapeutic target for antifolate drugs such as methotrexate; specifically, methotrexate polyglutamates potently inhibit the AICAR transformylase domain [4]. This inhibition leads to the intracellular accumulation of AICAR (ZMP), which subsequently promotes the release of the anti-inflammatory mediator adenosine (Cronstein & Aune, 2020) [4]. ATIC is also a target in oncology, where its inhibition helps suppress the rapid proliferation of cancer cells by depleting nucleotide pools (DrugBank) [5]. Genetic deficiency in the ATIC gene results in AICA-ribosiduria, a rare metabolic disorder characterized by profound neurological deficits (Marie et al., 2004) [3]. Consequently, ATIC is a key molecule in both the management of autoimmune diseases and the development of anti-neoplastic therapies [4, 5]. Note: The target name provided in the prompt conflates ATIC with Glycinamide ribonucleotide formyltransferase (GART), which is a separate enzyme in the same pathway.

Other names

5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolaseAICARFT/IMPCHPURHAICAR transformylaseIMP cyclohydrolase

Inhibition of the AICAR transformylase activity of the bifunctional enzyme, preventing the conversion of AICAR to FAICAR and subsequently IMP, leading to purine depletion and adenosine-mediated anti-inflammatory signaling [4, 5].