title: Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate.
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.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton, New Jersey 08544, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Xin
authors.initials: X
authors.lastname: Teng
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Mattaini
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Looper
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005977:Glutarates / Q000737:chemistry / Q000378:metabolism*; D005988:Glyceric Acids / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D050543:Phosphoglycerate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005977:Glutarates; D005988:Glyceric Acids; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; C005156:3-phosphoglycerate; D050543:Phosphoglycerate Dehydrogenase