ArticleNature metabolism2023
Allosteric regulation of CAD modulates de novo pyrimidine synthesis during the cell cycle.
Article in Nature metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- OTUD6A promotes de novo pyrimidine synthesis by deubiquitinating and stabilizing CAD in cervical cancer.Oncogene · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Dynamic control of nucleotide metabolism in physiology and disease.Nature cell biology · 2026Review
- Myricetin InhibitsCells · 2026Article
- Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.Nature metabolism · 2026Article
- The oncogenic control of nucleotide synthesis.Oncogenesis · 2026Review
- Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy.bioRxiv : the preprint server for biology · 2026Article
- Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.Nature communications · 2026Article
- Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.Frontiers in cell and developmental biology · 2026Review
- PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.Cancer research · 2025Article
- Conformational Dynamics of the Active Site Loop in Dihydroorotase Highlighting the Limitations of Loop-In Structures for Inhibitor Docking.International journal of molecular sciences · 2025Article
- C-type natriuretic peptide attenuates enhanced glycolysis and de novo pyrimidine synthesis in pericytes of patients with pulmonary arterial hypertension.Communications biology · 2025Article
- Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.Molecular cell · 2025Article
- LM2I leads to CAD ubiquitination and liver cancer suppression through activation of ASS1.Acta biochimica et biophysica Sinica · 2025Article
- The Loop-In Binding Mode of Dihydroorotase: Implications for Ligand Binding and Therapeutic Targeting.International journal of molecular sciences · 2025Review
- mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.Cell reports · 2025Article
- Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.Nature metabolism · 2024Article
- mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction.Cell reports · 2024Article
- CHIP promotes CAD ubiquitination and degradation to suppress the proliferation and colony formation of glioblastoma cells.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Hijacking of nucleotide biosynthesis and deamidation-mediated glycolysis by an oncogenic herpesvirus.Nature communications · 2024Article
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Abstract
Metabolism is a fundamental cellular process that is coordinated with cell cycle progression. Despite this association, a mechanistic understanding of cell cycle phase-dependent metabolic pathway regulation remains elusive. Here we report the mechanism by which human de novo pyrimidine biosynthesis is allosterically regulated during the cell cycle. Combining traditional synchronization methods and metabolomics, we characterize metabolites by their accumulation pattern during cell cycle phases and identify cell cycle phase-dependent regulation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase (CAD), the first, rate-limiting enzyme in de novo pyrimidine biosynthesis. Through systematic mutational scanning and structural modelling, we find allostery as a major regulatory mechanism that controls the activity change of CAD during the cell cycle. Specifically, we report evidence of two Animalia-specific loops in the CAD allosteric domain that involve sensing and binding of uridine 5'-triphosphate, a CAD allosteric inhibitor. Based on homology with a mitochondrial carbamoyl-phosphate synthetase homologue, we identify a critical role for a signal transmission loop in regulating the formation of a substrate channel, thereby controlling CAD activity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.