Lookup NU author(s): Judith Unterlass,
Dr Arnaud Basle,
Dr Julie Tucker,
Dr Celine Cano,
Professor Martin Noble,
Professor Nicola Curtin
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.
Author(s): Unterlass JE, Wood RJ, Basle A, Tucker J, Cano C, Noble MM, Curtin NJ
Publication type: Article
Publication status: Published
Online publication date: 06/11/2017
Acceptance date: 16/09/2017
ISSN (electronic): 1949-2553
Publisher: Impact Journals LLC
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