Journal
CELL DISCOVERY
Volume 7, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41421-020-00227-0
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Funding
- National Natural Science Foundation of China [32071190, 31870723]
- Chinese Academy of Sciences [XDB37030305]
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The study presents the crystal structures of D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) and analyzes its substrate specificity and catalytic reaction at a molecular level. Insights into the pathogenicity of disease-associated mutations are provided through structural and biochemical data.
D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) into 2-oxoglutarate, and genetic D-2-HGDH deficiency leads to abnormal accumulation of D-2-HG which causes type I D-2-hydroxyglutaric aciduria and is associated with diffuse large B-cell lymphoma. This work reports the crystal structures of human D-2-HGDH in apo form and in complexes with D-2-HG, D-malate, D-lactate, L-2-HG, and 2-oxoglutarate, respectively. D-2-HGDH comprises a FAD-binding domain, a substrate-binding domain, and a small C-terminal domain. The active site is located at the interface of the FAD-binding domain and the substrate-binding domain. The functional roles of the key residues involved in the substrate binding and catalytic reaction and the mutations identified in D-2-HGDH-deficient diseases are analyzed by biochemical studies. The structural and biochemical data together reveal the molecular mechanism of the substrate specificity and catalytic reaction of D-2-HGDH and provide insights into the pathogenicity of the disease-associated mutations.
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