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

DOI: 10.18632/oncotarget.22327 DOI Help

Authors: Judith E. Unterlass (Newcastle University) , Robert J. Wood (Cancer Research Technology) , Arnaud Basle (Newcastle University) , Julie Tucker (Newcastle University) , Céline Cano (Newcastle University) , Martin M. E. Noble (Newcastle University) , Nicola J. Curtin (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Oncotarget

State: Published (Approved)
Published: November 2017
Diamond Proposal Number(s): 9948

Open Access Open Access

Abstract: 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.

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

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography