Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite d-2-Hydroxyglutarate
Name
Human Phosphoglycerate Dehydrogenase.pdf
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Author(s)
Teng, Xin
Liu, Ling
Looper, Ryan E.
Rabinowitz, Joshua D.
Vander Heiden, Matthew G.
Mattaini, Katherine Ruth
Fan, Jing,M. Eng.Massachusetts Institute of Technology.
Date Issued
November 2014
Journal
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Citation
Fan, Jing et al. “Human Phosphoglycerate Dehydrogenase Produces the Oncometabolite d-2-Hydroxyglutarate.” ACS Chemical Biology 10.2 (2015): 510–516. CrossRef. Web. © 2014 American Chemical Society
Version
Final published version
Abstract
Human d-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthetic pathway, is genomically amplified in tumors including breast cancer and melanoma. In PHGDH-amplified cancer cells, knockdown of PHGDH is not fully rescued by exogenous serine, suggesting possible additional growth-promoting roles for the enzyme. Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of α-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). Knockdown of PHGDH decreased cellular 2HG by approximately 50% in the PHGDH-amplified breast cancer cell lines MDA-MB-468 (normal concentration 93 μM) and BT-20 (normal concentration 35 μM) and overexpression of PHGDH increased cellular 2HG by over 2-fold in non-PHGDH-amplified MDA-MB-231 breast cancer cells, which normally display very low PHGDH expression. The reduced 2HG level in PHGDH knockdown cell lines can be rescued by PHGDH re-expression, but not by a catalytically inactive PHGDH mutant. The initial connection between cancer and d-2HG involved production of high levels of d-2HG by mutant isocitrate dehydrogenase. More recently, however, elevated d-2HG has been observed in breast cancer tumors without isocitrate dehydrogenase mutation. Our results suggest that PHGDH is one source of this d-2HG.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1021/cb500683c
