5-phosphoribosyl 1-pyrophosphate (PRPP) synthetase (ATP:D-ribose-5-phosphate pyrophosphotransferase, EC 2.7.6.1) catalyses the formation of PRPP from ATP and ribose 5-phosphate. PRPP is an important substrate in the synthesis of nearly all nucleotides, and PRPP synthetase links the pentose phosphate pathway to the pyrimidine and purine de novo and salvage pathways, the biosynthesis of tryptophan and histidine, and pyridine nucleotide coenzymes.
In humans, an excess of PRPP synthetase activity results in disordered purine metabolism. Inherited PRPP synthetase overactivity is an X-linked disease associated with purine nucleotide and uric acid overproduction, gout, and neurodevelopmental impairment. The kinetic bases of enzyme overactivity include both regulatory defects as well as catalytic abnormalities.
PRPP synthetase exists as complexes consisting of two highly homologous catalytic subunits and other components, termed PRPP synthetase associated proteins (PAPs). The human PAP39 (Phosphoribosyl pyrophosphate synthetase-associated protein 1) shares 44 % sequence identity with the human PRPP synthetase catalytic domain. The presences of PAPs in the PRPP synthetase complexes inhibit the activity of the catalytic subunits.
The structure of PRPP synthetase from Bacillus subtilis has been determined previously. The current structure of human PAP39 reveals, as expected, an overall fold similar to that of the catalytic PRPP synthetase monomer. Moreover, PAP39 presents a similar hexameric arrangement to that observed for the Bacillus subtilis PRPP synthetase. In the PAP39 structure, the pocket corresponding to the terminal phosphate-binding site for the allosteric regulator ADP in the catalytic subunit is occupied by a sulphate ion, suggesting that this site might bind nucleotides also in PAP39.
