2. Academic Validation
  3. Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors

Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors

  • Cell Mol Life Sci. 2021 Dec 31;79(1):27. doi: 10.1007/s00018-021-04022-2.
Yuping Tan  # 1,  Xia Zhou  # 2,  Yanqiu Gong  # 3,  Kun Gou 2,  Youfu Luo 1,  Da Jia 4,  Lunzhi Dai 5,  Yinglan Zhao 6,  Qingxiang Sun 7
Affiliations

Affiliations

  • 1 Department of Pathology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China.
  • 3 National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
  • 4 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Division of Neurology, Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. [email protected].
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, 17#, 3rd Section, Ren min South Road, Chengdu, 610041, China. [email protected].
  • 7 Department of Pathology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. [email protected].
  • # Contributed equally.
PMID: 34971423 DOI: 10.1007/s00018-021-04022-2
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.

Keywords

Allosteric inhibition; Cancer mutation; Compound screening; Nucleotide-binding domain; Protein degradation.

Figures
Products