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

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.

SUBMITTER: Jin S

PROVIDER: S-EPMC10589216 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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

Jin Shan S Chen Xingchen X Yang Jun J Ding Jianping J

Nature communications 20231020 1

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, Mn<sup>2+</sup> and a series of substrates or products. We demonstrate that mLDHD is an Mn<sup>2+</sup>-dependent general dehydrogenase which exhibits cat ...[more]

PMID: 37863926

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Project description:IntroductionThere is no denying the clinical benefits of exogenous pyruvate in the treatment of pathological metabolic acidosis. However, whether it can prevent exercise physiological metabolic acidosis, delay the occurrence of exercise fatigue, and improve the beneficial effects of exercise and its internal mechanism remain unclear.MethodsWe randomly divided 24 male SD rats into 3 groups: one group was a control without exercise (CC, n = 8), and the other two groups were supplemented with 616 mg/kg/day pyruvate (EP, n = 8) or distilled water of equal volume (EC, n = 8). These groups completed acute high-intensity interval exercise (HIIE) after 7 days of supplementation. The acid metabolism variables were measured immediately after exercise including blood pH (pHe), base excess (BE), HCO3 -, blood lactic acid and skeletal muscle pH (pHi). The redox state was determined by measuring the oxidized coenzyme I/reduced coenzyme I (nicotinamide adenine dinucleotide [NAD+]/reduced NAD+ [NADH]) ratio and lactate/pyruvate (L/P) ratio. In addition, the activities of lactate dehydrogenase A (LDHA), hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) were determined by ELISA.ResultsPyruvate supplementation significantly reversed the decrease of pHe, BE, HCO3 - and pHi values after HIIE (p < 0.001), while significantly increased the activities of LDHA (p = 0.048), HK (p = 0.006), and PFK (p = 0.047). Compared with the CC, the NAD+/NADH (p = 0.008) ratio and the activities of LDHA (p = 0.002), HK (p < 0.001), PFK (p < 0.001), and PK (p = 0.006) were significantly improved in EP group.DiscussionThis study provides compelling evidence that oral pyruvate attenuates HIIE-induced intracellular and extracellular acidification, possibly due to increased activity of LDHA, which promotes the absorption of H+ in the LDH reaction. The beneficial effects of improving the redox state and glycolysis rate were also shown. Our results suggest that pyruvate can be used as an oral nutritional supplement to buffer HIIE induced metabolic acidosis.

Dataset Information

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

Publications

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

Similar Datasets

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