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Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis

Author

Listed:
  • Shan Jin

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Xingchen Chen

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Jun Yang

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences)

  • Jianping Ding

    (University of Chinese Academy of Sciences, Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Mammalian lactate dehydrogenase D (LDHD) catalyzes the oxidation of D-lactate to pyruvate. LDHD mutations identified in patients with D-lactic acidosis lead to deficient LDHD activity. Here, we perform a systematic biochemical study of mouse LDHD (mLDHD) and determine the crystal structures of mLDHD in FAD-bound form and in complexes with FAD, Mn2+ and a series of substrates or products. We demonstrate that mLDHD is an Mn2+-dependent general dehydrogenase which exhibits catalytic activity for D-lactate and other D-2-hydroxyacids containing hydrophobic moieties, but no activity for their L-isomers or D-2-hydroxyacids containing hydrophilic moieties. The substrate-binding site contains a positively charged pocket to bind the common glycolate moiety and a hydrophobic pocket with some elasticity to bind the varied hydrophobic moieties of substrates. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of LDHD, and the functional roles of mutations in the pathogenesis of D-lactic acidosis.

Suggested Citation

  • Shan Jin & Xingchen Chen & Jun Yang & Jianping Ding, 2023. "Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42456-3
    DOI: 10.1038/s41467-023-42456-3
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    1. Glen R. Monroe & Albertien M. van Eerde & Federico Tessadori & Karen J. Duran & Sanne M. C. Savelberg & Johanna C. van Alfen & Paulien A. Terhal & Saskia N. van der Crabben & Klaske D. Lichtenbelt & S, 2019. "Identification of human D lactate dehydrogenase deficiency," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
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