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Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH)

Lookup NU author(s): Judith Unterlass, Dr Arnaud Basle, Dr Julie Tucker, Dr Celine CanoORCiD, Professor Martin NobleORCiD, Professor Nicola CurtinORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© Unterlass et al. Cancer cells reprogram their metabolism and energy production to sustain increased growth, enable metastasis and overcome resistance to cancer treatments. Although primary roles for many metabolic proteins have been identified, some are promiscuous in regards to the reaction they catalyze. To efficiently target these enzymes, a good understanding of their enzymatic function and structure, as well as knowledge regarding any substrate or catalytic promiscuity is required. Here we focus on the characterization of human 3-phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyzes the NAD+-dependent conversion of 3-phosphoglycerate to phosphohydroxypyruvate, which is the first step in the de novo synthesis pathway of serine, a critical amino acid for protein and nucleic acid biosynthesis. We have investigated substrate analogues to assess whether PHGDH might possess other enzymatic roles that could explain its occasional over-expression in cancer, as well as to help with the design of specific inhibitors. We also report the crystal structure of the catalytic subunit of human PHGDH, a dimer, solved with bound cofactor in one monomer and both cofactor and L-tartrate in the second monomer. In vitro enzyme activity measurements show that the catalytic subunit of PHGDH is still active and that PHGDH activity could be significantly inhibited with adenosine 5'-diphosphoribose.

Publication metadata

Author(s): Unterlass JE, Wood RJ, Basle A, Tucker J, Cano C, Noble MM, Curtin NJ

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2017

Volume: 8

Issue: 61

Pages: 104478-104491

Online publication date: 06/11/2017

Acceptance date: 16/09/2017

Date deposited: 15/12/2017

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC


DOI: 10.18632/oncotarget.22327


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