Research Papers:

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

Judith E. Unterlass _, Robert J. Wood, Arnaud Baslé, Julie Tucker, Céline Cano, Martin M.E. Noble and Nicola J. Curtin

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Oncotarget. 2017; 8:104478-104491. https://doi.org/10.18632/oncotarget.22327

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Judith E. Unterlass1,5, Robert J. Wood2, Arnaud Baslé3, Julie Tucker1, Céline Cano4, Martin M.E. Noble1 and Nicola J. Curtin1

1Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK

2Cancer Research Technology, Discovery Laboratories, Babraham Research Campus, Cambridge, UK

3Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK

4Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, UK

5Present address: Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Correspondence to:

Judith E. Unterlass, email: [email protected]

Keywords: 3-phosphoglycerate dehydrogenase; substrate and cofactor specificity; serine synthesis

Received: September 13, 2017    Accepted: September 16, 2017    Published: November 06, 2017


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.

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