D-Lactate Metabolism in Clinical Conditions

D-lactate is the stereoisomer of L-lactate that arises primarily through microbial fermentation in the gut and via the glyoxalase pathway in human tissues. Under normal circumstances, low levels of circulating D-lactate are cleared by a specialised mitochondrial enzyme, lactate dehydrogenase D (LDHD), converting D-lactate into pyruvate for entry into central metabolism. However, disruptions such as short bowel syndrome, congenital defects in LDHD, or overgrowth of D-lactate–producing bacteria can overwhelm clearance mechanisms and lead to D-lactic acidosis. Clinically, this manifests as intermittent neurocognitive symptoms, motor disturbances and, in extreme cases, cardiac compromise. Recent advances in structural biology have elucidated the molecular basis of LDHD function and its dependence on metal cofactors, while emerging analytical techniques are enhancing early detection of D-lactate in plasma. Understanding D-lactate dynamics is vital for diagnosing rare metabolic disorders, optimising management of critical illness and exploring its role as a biomarker in infectious and non-infectious conditions.

Research from Nature Portfolio

Recent studies have defined the structural and mechanistic underpinnings of D-lactate oxidation by mammalian LDHD. High-resolution crystallography has revealed a dual-pocket substrate-binding site with discrete charged and hydrophobic regions that confer strict stereospecificity for D-lactate and related hydroxyacids. Biochemical assays demonstrated metal-ion dependence, highlighting the essential role of manganese in catalytic turnover. Parallel genetic analyses identified loss-of-function variants in human LDHD, linking deficient enzyme activity to episodes of D-lactic acidosis in patients with short bowel physiology. Functional rescue experiments in model organisms confirmed that wild-type LDHD restores normal D-lactate clearance, whereas pathogenic variants fail to prevent accumulation. These findings establish LDHD as the principal determinant of D-lactate homeostasis in mammals and open avenues for genotype-directed diagnostics and potential enzyme-targeted therapies.

D-Lactate Metabolism in Clinical Conditions publication trend

The graph below shows the total number of articles in d-lactate metabolism in clinical conditions across all publications each year (not limited to Nature Index journals).

Technical terms

D-lactate: The D-stereoisomer of lactic acid produced by gut microbes and by the glyoxalase pathway in human cells.

D-lactic acidosis: A metabolic condition characterized by elevated D-lactate levels leading to acid–base imbalance, neurological symptoms and potential cardiac effects.

Lactate dehydrogenase D (LDHD): A mitochondrial enzyme that specifically oxidises D-lactate to pyruvate, requiring metal cofactors for activity.

Glyoxalase pathway: A metabolic route detoxifying methylglyoxal to D-lactate via sequential action of glyoxalase I and II.

References

1. Lactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis. Nature Communications (2023).
2. Early detection of plasma d-lactate: Toward a new highly-specific biomarker of bacteraemia?. Heliyon (2023).
3. Identification of human D lactate dehydrogenase deficiency. Nature Communications (2019).
4. Lactic Acidosis Related to Pharmacotherapy and Human Diseases. Pharmaceuticals (2022).
5. High anion gap metabolic acidosis caused by D-lactate: mind the time of blood collection. Biochemia Medica (2020).