Phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS)

Phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is a bifunctional enzyme that catalyzes the sixth and seventh steps of the de novo purine biosynthesis pathway. It is responsible for the conversion of 5-aminoimidazole ribonucleotide (AIR) to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR), and subsequently to N-succinylo-5-aminoimidazole-4-carboxamide ribonucleotide (SAICAR) [UniProt, P22234]. This enzyme is vital for the production of inosine monophosphate (IMP), the precursor for adenine and guanine nucleotides essential for DNA and RNA synthesis [NCBI Gene, 10606]. In many cancers, PAICS is significantly overexpressed to support the high metabolic demands of rapid cell proliferation, a phenomenon often referred to as purine addiction [Nature Communications, 2017]. Because normal cells can often fulfill their purine requirements through the salvage pathway, PAICS represents a selective therapeutic vulnerability in oncology [Journal of Cancer, 2020]. Inhibiting PAICS leads to the depletion of intracellular nucleotide pools, induction of DNA damage, and eventual apoptotic cell death in tumor cells [Oncotarget, 2015]. Research into small-molecule inhibitors of PAICS is ongoing, with several compounds showing efficacy in preclinical models of lung, prostate, and bladder cancer.

Other names

ADE2ADE2H1AIRCPAISMultifunctional protein ADE2AIR carboxylaseSAICAR synthetase

Inhibition of the AIR carboxylase or SAICAR synthetase domains of the PAICS enzyme, leading to the depletion of de novo purine nucleotides and subsequent inhibition of DNA/RNA synthesis.