Metabolic functions of misunderstood D-2-hydroxyglutarate

Abstract

<p>Isocitrate dehydrogenase mutation-induced D-2-hydroxyglutarate (D-2-HG) accumulation may promote the tumorigenesis of numerous cancers. D-2-HG produced by several promiscuous enzymatic reactions under normal conditions is also toxic to organisms. D-2-HG was thus previously viewed as an abnormal metabolite with no physiological function and D-2-HG conversion to 2-ketoglutarate by D-2-HG dehydrogenase seems to be a process of metabolite repair. However, several recent studies have revealed that D-2-HG production is not a meaningless process without a physiological purpose. D-2-HG production actually participates in many core metabolic processes, and disorders of these processes may be the reason for the D-2-HG accumulation in some tumors lacking the isocitrate dehydrogenase mutation. This review summarizes the diverse and widely distributed metabolic processes involving D-2-HG, highlights the physiological functions of D-2-HG generation from various precursors, and discusses the possible applications of enzymes related to D-2-HG metabolism in synthetic biology, diagnosis, and treatment of D-2-HG accumulation-induced diseases.</p>