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

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

  • Nat Cell Biol. 2023 Jun 8. doi: 10.1038/s41556-023-01146-4.
Chuanzhen Yang # 1,  Yiliang Zhao # 1,  Liao Wang # 1 2,  Zihao Guo 1,  Lingdi Ma 1,  Ronghui Yang 3,  Ying Wu 1,  Xuexue Li 3,  Jing Niu 1,  Qiaoyun Chu 1,  Yanxia Fu 1,  Binghui Li 4 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 2 Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
  • 3 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. bli@ccmu.edu.cn.
  • 5 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China. bli@ccmu.edu.cn.
  • 6 Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. bli@ccmu.edu.cn.
  • # Contributed equally.
PMID: 37291265 DOI: 10.1038/s41556-023-01146-4
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.

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