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The conserved vertebrate function of LDHD is oxidation of D-lactate to pyruvate,
with high stereoselectivity for D- over L-lactate; in zebrafish, ldhd
loss-of-function selectively elevates D-lactate while L-lactate is unchanged.
"The conserved vertebrate function of LDHD is **oxidation of D-lactate to pyruvate**. In zebrafish, the essential in vivo readout is that **ldhd loss-of-function increases D-lactate levels while L-lactate remains unchanged**, demonstrating stereospecificity for D-lactate metabolism."
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Beyond D-lactate, vertebrate LDHD acts more broadly as a general FAD-dependent
dehydrogenase for hydrophobic D-2-hydroxyacids, with no activity on the
corresponding L-isomers.
"Beyond D-lactate, vertebrate LDHD acts more broadly on **D-2-hydroxyacids**."
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Mammalian LDHD is an FAD-containing flavoprotein and is Mn2+-dependent, with
activity highest in the presence of Mn2+ divalent metal ions.
"* **FAD-containing (flavoprotein):** purified enzyme has the yellow color and absorbance features expected for FAD; a reported FAD:protein molar ratio is **0.73 ± 0.04**. (jin2023lactatedehydrogenased pages 1-2)"
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Vertebrate LDHD is consistently described as mitochondrial and associated with
the mitochondrial inner membrane.
"Vertebrate LDHD is consistently described as **mitochondrial** and associated with the **mitochondrial inner membrane**."
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The zebrafish ldhd knockout allele sa15623 yields an adult-viable, fertile line
whose embryos accumulate D-lactate; the phenotype is rescued by wild-type human
LDHD mRNA but not patient-variant mRNAs, establishing LDHD enzymatic loss of
function as causal.
"The central zebrafish functional evidence comes from a zebrafish **ldhd** knockout allele (**sa15623**) that disrupts an essential splice site and yields an **ldhd−/− line that is adult viable and fertile**."
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A 2024 study provided direct evidence that human LDHD transfers electrons from
D-lactate to cytochrome c, supporting mitochondrial membrane polarization and
linking LDHD to mitochondrial redox physiology.
"A 2024 study provided direct evidence that **human LDHD transfers electrons from D-lactate to cytochrome c**, thereby supporting mitochondrial membrane polarization."
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LDHD functions as part of metabolite repair, clearing D-lactate generated
endogenously downstream of the methylglyoxal/glyoxalase pathway and potentially
other D-2-hydroxyacids.
"LDHD is discussed as part of the broader concept of **metabolite repair**, in which enzymes prevent accumulation of side-products and damaged metabolites; in this view, mitochondrial LDHD clears D-lactate and potentially other D-2-hydroxyacids."