The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here we determine structures of human PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.

普遍保守的磷酸核糖焦磷酸合成酶（PRPS）在进化多样的生物体中组装丝。 PRPS 是核苷酸代谢的关键调节因子，人类酶 PRPS1 的突变会导致一系列疾病。在这里，我们确定了处于活性和抑制状态的人类 PRPS1 丝的结构，以及适应这两种构象的固定组装接触。保守的组装界面稳定了必需磷酸激活剂的结合位点，从而增加了丝状体的活性。一些疾病突变会改变组装，支持丝稳定性和活性之间的联系。活性 PRPS1 丝翻转底物的结构也揭示了一个活性位点的催化作用与邻近位点的产物释放的耦合。因此，PRPS1 丝提供了额外的变构控制层，在整个进化过程中都保持不变，可能对代谢稳态产生影响。通过聚合来稳定变构结合位点增加了基于组装的酶调节机制的多样性。