NUDT5通过与PPAT相互作用调节嘌呤代谢和硫嘌呤敏感性，这一成果由得克萨斯大学
课题组人员发现Nudix水解酶5 （NUDT5）是DNPB调节因子。在嘌呤回收过程中，NUDT5通过与DNPB途径中的限速酶磷酸核糖基焦磷酸氨基转移酶（PPAT）相互作用，独立于其催化功能抑制DNPB。NUDT5-PPAT相互作用促进PPAT寡聚，抑制PPAT的酶活性，促进嘌呤酶体的分解，这是一种在DNPB中起作用的代谢产物。破坏NUDT5-PPAT相互作用克服了嘌呤回收过程中DNPB的抑制，允许DNPB过量并诱导硫嘌呤耐药性。因此，NUDT5控制DNPB和救助之间的平衡，以维持适当的细胞嘌呤核苷酸浓度。
据悉，细胞通过从头嘌呤生物合成（DNPB）和嘌呤回收产生嘌呤核苷酸。嘌呤救助抑制DNPB以防止过量嘌呤核苷酸合成，其机制尚不完全清楚。
附：英文原文
Title: NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT
Author: Zheng Wu, Phong T Nguyen, Varun Sondhi, Run-Wen Yao, Zhifang Lu, Tao Dai, Jui-Chung Chiang, Feng Cai, Imani M Williams, Eliot B Blatt, Zengfu Shang, Ling Cai, Jing Zhang, Mya D Moore, Islam Alshamleh, Xiangyi Li, Tamaratare Ogu, Lauren G Zacharias, Rainah Winston, Joao S Patricio, Xandria Johnson, Wei-Min Chen, Qian Cong, Thomas P Mathews, Yuanyuan Zhang, Limei Zhang, Ralph J DeBerardinis
Issue&Volume: 2025-11-06
Abstract: Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that are incompletely understood. We identified Nudix hydrolase 5 (NUDT5) as a DNPB regulator. During purine salvage, NUDT5 suppresses DNPB independently of its catalytic function but through interaction with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme in the DNPB pathway. The NUDT5-PPAT interaction promoted PPAT oligomerization, suppressed PPAT’s enzymatic activity, and facilitated disassembly of the purinosome, a metabolon that functions in DNPB. Disrupting the NUDT5-PPAT interaction overcame DNPB suppression during purine salvage, permitting excessive DNPB and inducing thiopurine resistance. Therefore, NUDT5 governs the balance between DNPB and salvage to maintain appropriate cellular purine nucleotide concentrations.
DOI: adx9717
Source: https://www.science.org/doi/10.1126/science.adx9717