title: L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH.
abstract: The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Hardik
authors.identifier: 0000-0001-8408-5686
authors.initials: H
authors.lastname: Shah
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Carmona-Fontaine
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ariën S
authors.initials: AS
authors.lastname: Rustenburg
authors.affiliation: Physics Department, City College of New York, New York, New York, USA.
authors.forename: Salah
authors.initials: S
authors.lastname: Salah
authors.affiliation: Physics Department, City College of New York, New York, New York, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Gunner
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chodera
authors.affiliation: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D055162:Biocatalysis; D008401:Gas Chromatography-Mass Spectrometry; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism
chemical_list: D005977:Glutarates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D007770:L-Lactate Dehydrogenase; D008291:Malate Dehydrogenase