Nature Cell Biology
Nature Cell Biology
a year ago

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

De novo pyrimidine biosynthetic complexes support cancer cell proliferation and ferroptosis defence
Chuanzhen Yang, Yiliang Zhao, Liao Wang, Zihao Guo, Lingdi Ma, Ronghui Yang, Ying Wu, Xuexue Li, Jing Niu, Qiaoyun Chu, Yanxia Fu, Binghui Li
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.

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

DOI: 10.1038/s41556-023-01146-4

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