Chiral LC-MS/MS of D- and L-2-Hydroxyglutaric Acid Biomarkers

Introduction

For example, the TCA cycle of a cancer cell showing the buildup of 2-OHG is depicted in Figure 1. The chiral differentiation and quantification of _D-2-OHG and _L-2-OHG is key for characterizing neurometabolic disorders like the 2-hydroxyglutaric acidurias that cause neurological impairment early in life.¹ In patients with brain tumors, mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are found in approximately 80% of grade II-III gliomas and secondary glioblastomas. The demonstration that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate (2-ketoglutarate) to the oncometabolite _D-2-OHG represents a milestone event in cancer biology (see Figure 2).² Cancer-associated IDH mutations in IDH1 and IDH2 across glioma as well as several hematologic malignancies have become of prognostic interest and for biomarkers and therapeutic opportunities.³