ArticleCellular and molecular life sciences : CMLS2021
Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors.
Article in Cellular and molecular life sciences : CMLS, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 19 citations in OpenAlex.
- Molecular mechanisms of transhydrogenase activity and allosteric regulation in eukaryotic type II PHGDH Ser33.Nature communications · 2026Article
- Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform.Journal of the American Chemical Society · 2025Article
- Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists.Acta pharmaceutica Sinica. B · 2025Article
- Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH.Acta pharmaceutica Sinica. B · 2024Article
- Cycling back to folate metabolism in cancer.Nature cancer · 2024Review
- PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.Cancer research · 2024Article
- Article
- Targeting allosteric regulation of cancer metabolism.Nature chemical biology · 2022Review
- Metabolomic analysis of vascular cognitive impairment due to hepatocellular carcinoma.Frontiers in neurology · 2022Article
- The role of serine metabolism in lung cancer: From oncogenesis to tumor treatment.Frontiers in genetics · 2022Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy. Here, oridonin was identified from a natural product library as a new PHGDH inhibitor. The crystal structure of PHGDH in complex with oridonin revealed a new allosteric site. The binding of oridonin to this site reduced the activity of the enzyme by relocating R54, a residue involved in substrate binding. Mutagenesis studies showed that PHGDH activity was very sensitive to cysteine mutations, especially those in the substrate binding domain. Conjugation of oridonin and other reported covalent PHGDH inhibitors to these sites will therefore inhibit PHGDH. In addition to being inhibited enzymatically, PHGDH can also be inhibited by protein aggregation and proteasome-mediated degradation. Several tested PHGDH cancer mutants showed altered enzymatic activity, which can be explained by protein structure and stability. Overall, the above studies present new biophysical and biochemical insights into PHGDH and may facilitate the future design of PHGDH inhibitors.
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