Glutamine phosphoribosyl pyrophosphate amidotransferase (PPAT)

Glutamine phosphoribosyl pyrophosphate amidotransferase (PPAT), also known as GPAT, is the rate-limiting enzyme in the de novo purine biosynthetic pathway (UniProt P12259). It catalyzes the conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) and glutamine into 5-phosphoribosyl-1-amine, representing the first committed step in the synthesis of inosine monophosphate (IMP) (NCBI Gene 5471). Because rapidly dividing cells, such as cancer cells and activated immune cells, have a high demand for purine nucleotides for DNA and RNA synthesis, PPAT serves as a critical metabolic target (StatPearls NBK546601). The enzyme is subject to complex allosteric regulation, being activated by its substrate PRPP and inhibited by the end-products of the pathway, adenosine and guanosine nucleotides (UniProt P12259). Pharmacologically, PPAT is targeted by thiopurine drugs like 6-mercaptopurine and azathioprine, which are metabolized into thio-nucleotide analogs that act as feedback inhibitors of the enzyme (DrugBank DB01033). Dysregulation of PPAT activity is clinically linked to hyperuricemia and gout due to the overproduction of purines, as well as various malignancies where the enzyme is often upregulated to support rapid proliferation (StatPearls NBK546601).

Other names

AmidophosphoribosyltransferasePhosphoribosylpyrophosphate amidotransferaseGPATGlutamine-PRPP amidotransferaseATA

Allosteric feedback inhibition by purine nucleotide analogs