Enzymes of de novo purine synthesis (DNPS enzymes)

The enzymes of de novo purine synthesis (DNPS) constitute a critical metabolic pathway responsible for the stepwise assembly of the purine ring, starting from phosphoribosyl pyrophosphate (PRPP) to form inosine monophosphate (IMP) [1.2.1, 1.4.3]. In humans, this process involves six enzymes, several of which are multifunctional, such as the trifunctional GART and bifunctional ATIC [1.2.1, 1.4.2]. These enzymes often organize into a dynamic multi-enzyme complex known as the purinosome to enhance catalytic efficiency through substrate channeling [1.4.2]. This pathway is essential for providing the adenine and guanine nucleotides required for DNA replication, RNA transcription, and energy metabolism, making it a primary target in rapidly proliferating cells [1.2.2, 1.4.1]. Consequently, DNPS inhibitors such as methotrexate and 6-mercaptopurine have long been cornerstones of cancer chemotherapy and immunosuppressive therapy for autoimmune diseases [1.3.1, 1.5.5]. Beyond oncology and immunology, these enzymes are increasingly explored as targets for novel anti-infectives, particularly against pathogens like Mycobacterium tuberculosis that rely heavily on de novo synthesis [1.3.3, 1.3.4]. Therapeutic use is often limited by systemic toxicities, such as myelosuppression and gastrointestinal distress, due to the pathway's fundamental role in normal high-turnover tissues [1.5.1, 1.5.3].

Other names

Purine biosynthetic pathway enzymesPurinosomeDe novo purine nucleotide biosynthesis enzymesDNPNB enzymesDNPS enzymes

Inhibition of specific enzymes within the de novo purine biosynthetic pathway (such as PPAT, GART, ATIC, or IMPDH) to deplete intracellular pools of adenine and guanine nucleotides, thereby disrupting DNA/RNA synthesis and inducing cell cycle arrest or apoptosis [1.3.2, 1.5.4].