The homeostatic maintenance of metabolic networks involves two major components: the catalytically active metabolic enzymes and the homeostatic metabolite molecules. We have been working on the regulation of α-KG-related metabolic pathways, including the transamination pathway and IDH-related pathway, focusing on the post-translational modification of α-KG pathway-related metabolic enzymes and the involvement of metabolic small molecules in epigenetic regulation, and found that the abnormal regulation of these two links is closely related to tumor’s development.
The main findings were that (1) acetylation modification of metabolic enzyme GOT2 (aspartate aminotransferase), which affects the binding status of GOT2 to MDH2 (malate dehydrogenase) protein, regulates the efficiency of mitochondrial malate-aspartate shuttle pathway system and affects the cellular oxidation-reduction status and tumor’s growth of pancreatic cancer cells (EMBO J, 2015). (2) Oncogenic mechanism of metabolic enzyme IDH mutations. IDH mutations produce the oncogenic metabolite 2-hydroxyglutarate (2-HG), which is structurally α-KG-like and competitively inhibits dioxygenases that use α-KG as a substrate, including the histone demethylases KDM and TET family 5-methylcytosine hydroxylases, altering epigenetic and downstream gene transcription, leading to tumorigenesis (Cancer Cell, cover article, 2011). The main contribution of the candidate is the discovery that mutations in the metabolic enzyme IDH inhibit the DNA-demethylating enzyme TET.(3) α-KG dynamically regulates DNA demethylation. In mice, exogenous nutrients induce changes in α-KG levels that dynamically regulate DNA demethylase TET activity and regulate downstream target gene transcription (Cell Research, 2014).
Our study is the first to report that metabolites, as passive products of metabolic enzyme-catalyzed reactions, can act as "signaling molecules" that regulate epigenetic modifications and cellular signaling, and are an important link in maintaining the "homeostasis" of cellular metabolic networks
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