首都医科大学Binghui Li研究小组的最新研究表明，嘧啶从头生物合成复合物为癌细胞增殖和抵抗铁死亡提供支持。这一研究成果发表在2023年6月8日出版的国际学术期刊《自然—细胞生物学》杂志上。

研究人员表明胞质谷氨酸草酰乙酸转氨酶1与二氢乳清酸酶（CAD）和尿苷5′-单磷酸合酶（UMPS）形成复合物，然后该复合物与线粒体二氢乳清酸脱氢酶（DHODH）连接，DHODH由线粒体外膜蛋白电压依赖性阴离子选择性通道蛋白3介导。因此，这些蛋白质形成一种多酶复合物，称为“嘧啶小体”，AMP活化蛋白激酶（AMPK）作为调节因子。活化的AMPK从复合物中解离以增强嘧啶小体组装，但失活的UMPS会促进DHODH介导的铁死亡防御。同时，AMPK表达较低的癌细胞更依赖于嘧啶酶体介导的UMP生物合成，并且更容易受到其抑制。

该研究结果揭示了嘧啶酶体在调节嘧啶合成和铁死亡中的作用，并证明靶向嘧啶体是潜在的癌症治疗策略。

研究人员表示，嘧啶从头生物合成是由胞质氨基甲酰磷酸合成酶II、天冬氨酸甲酰转氨酶、CAD、UMPS以及DHODH催化产生的。 然而，尚不知道这些酶是如何协作完成这一反应的。

附：英文原文

Title: De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence

Author: Yang, Chuanzhen, Zhao, Yiliang, Wang, Liao, Guo, Zihao, Ma, Lingdi, Yang, Ronghui, Wu, Ying, Li, Xuexue, Niu, Jing, Chu, Qiaoyun, Fu, Yanxia, Li, Binghui

Issue&Volume: 2023-06-08

Abstract: De novo pyrimidine biosynthesis is achieved by cytosolic carbamoyl-phosphate synthetase II, aspartate transcarbamylase and dihydroorotase (CAD) and uridine 5′-monophosphate synthase (UMPS), and mitochondrial dihydroorotate dehydrogenase (DHODH). However, how these enzymes are orchestrated remains enigmatical. Here we show that cytosolic glutamate oxaloacetate transaminase 1 clusters with CAD and UMPS, and this complex then connects with DHODH, which is mediated by the mitochondrial outer membrane protein voltage-dependent anion-selective channel protein 3. Therefore, these proteins form a multi-enzyme complex, named ‘pyrimidinosome’, involving AMP-activated protein kinase (AMPK) as a regulator. Activated AMPK dissociates from the complex to enhance pyrimidinosome assembly but inactivated UMPS, which promotes DHODH-mediated ferroptosis defence. Meanwhile, cancer cells with lower expression of AMPK are more reliant on pyrimidinosome-mediated UMP biosynthesis and more vulnerable to its inhibition. Our findings reveal the role of pyrimidinosome in regulating pyrimidine flux and ferroptosis, and suggest a pharmaceutical strategy of targeting pyrimidinosome in cancer treatment.

DOI: 10.1038/s41556-023-01146-4

Source: https://www.nature.com/articles/s41556-023-01146-4