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

• Published in: Nature cell biology Vol. 25; no. 6; pp. 836 - 847
• Main Authors: Yang, Chuanzhen, Zhao, Yiliang, Wang, Liao, Guo, Zihao, Ma, Lingdi, Yang, Ronghui, Wu, Ying, Li, Xuexue, Niu, Jing, Chu, Qiaoyun, Fu, Yanxia, Li, Binghui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2023; Nature Publishing Group
• Subjects: 13/106; 13/95; 38/1; 631/67/2327; 631/80/82; 631/80/83; 64/60; AMP-activated protein kinase; AMP-Activated Protein Kinases; Biomedical and Life Sciences; Biosynthesis; Cancer; Cancer Research; Cell Biology; Cell growth; Cell Proliferation; Cell survival; Dehydrogenase; Dehydrogenases; Developmental Biology; Dihydroorotase; Dihydroorotate Dehydrogenase; Ferroptosis; Kinases; Life Sciences; Membrane proteins; Neoplasms; Phosphates; Proteins; Pyrimidines - pharmacology; Stem Cells; Transaminase; Uridine; Uridine monophosphate
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/s41556-023-01146-4

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. Yang, Zhao, Wang and colleagues identify and characterize a pyrimidine biosynthetic complex pyrimidinosome that is regulated by AMP-activated protein kinase and facilitates dihydroorotate dehydrogenase-mediated ferroptosis resistance, thereby regulating cancer cell proliferation and survival.