Oxaloacetate and PQQ as potent anti lactate agents
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Oxaloacetate (OAA) inhibits lactate dehydrogenase (LDH), lowering lactate by blocking pyruvate conversion to lactate. This spares NADH for oxidation back to NAD+ in mitochondria via shuttles.
OAA also directly oxidizes NADH to NAD+ through malate dehydrogenase (OAA to malate). Additionally, elevated OAA pulls acetyl-CoA into the TCA cycle via citrate synthase, lowering free acetyl-CoA—which reduces PDH inhibition (by product inhibition and PDK activation), thereby activating PDH—while raising free CoA.
Effects on Warburg Effect
OAA counters the Warburg effect by inhibiting LDH to cut lactate production, shifting metabolism from aerobic glycolysis toward oxidative phosphorylation.
NAD+/NADH Boost
OAA is converted to malate in the cytoplasm by malate dehydrogenase, consuming NADH to generate NAD+ and boosting the NAD+/NADH ratio by up to 900%, favoring pyruvate over lactate formation.
Reverses Metabolic Shifts In high-glycolysis states like cancer or chronic fatigue syndrome, OAA reduces excess lactic acid and lowers the lactate-to-pyruvate ratio, restoring oxidative metabolism.
Liver Injury Benefits
In liver damage models, OAA decreases lactic acid production to 53–85% of control levels, supporting metabolic recovery.PQQ counteracts lactate accumulation, Warburg metabolism, and reductive stress primarily by binding to lactate dehydrogenase (LDH) and shifting its equilibrium toward pyruvate production over lactate. This mechanism favors oxidative metabolism, reduces glycolytic reliance, and supports a more oxidized cellular state.
Anti-Lactate Action
PQQ oxidizes NADH to NAD+, inhibiting LDH's forward reaction (pyruvate → lactate) while enhancing the reverse (lactate → pyruvate). In cell studies, 50 nM PQQ cut lactate release by ~85% in fibroblasts, lowering lactate/pyruvate ratios and boosting ATP via TCA cycle entry. -
@user73636 said in Oxaloacetate and PQQ as potent anti lactate agents:
Oxaloacetate
The issue is (as with a lot of other biomolecules), this will instantly get turned into citric acid
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While a portion of OAA is indeed converted to citrate, this is actually a feature, not a bug, of its anti-lactate profile:
Clearing the Bottleneck: By converting to citrate, OAA "pulls" Acetyl-CoA into the TCA cycle.
Activating PDH: High levels of Acetyl-CoA normally inhibit Pyruvate Dehydrogenase (PDH). When OAA clears that Acetyl-CoA out by turning it into citrate, it "unlocks" PDH.
Result: Pyruvate is now more likely to be converted into Acetyl-CoA (to feed the cycle) rather than being "shunted" into lactate.Cytoplasmic vs. Mitochondrial Activity
The anti-lactate effects described in studies from exogenous OAA often occur in the cytoplasm before the OAA even reaches the mitochondria:
The Redox Buffer: In the cytoplasm, OAA effectively starves the LDH enzyme of its necessary fuel as they both compete for use of nadh
The Malate Shuttle: The resulting Malate then enters the mitochondria, effectively "shuttling" those electrons in for oxidative phosphorylation rather than letting them fester as "reductive stress" in the cytoplasm.Kinetic Inhibition of LDH
OAA is a structural analogue of pyruvate. Because of this similarity, it can act as a competitive inhibitor of Lactate Dehydrogenase (LDH). Even if it eventually gets metabolized, its presence in the cellular pool interferes with the enzyme's ability to bind to pyruvate and create lactate.You are correct that OAA is highly unstable and metabolically "hungry." This is why OAA supplementation often requires higher doses or stabilized forms (like thermally stabilized anhydrous OAA) to ensure enough reaches the target tissues before being decarboxylated or converted.
OAA's instability (spontaneous decarboxylation to pyruvate + CO2, half-life ~minutes at pH 7.4) necessitates stabilized forms like benaGene (anhydrous OAA) at 100-500mg doses for therapeutic levels, ensuring cytoplasmic delivery before mitochondrial uptake or decay. This supports the observed lactate drops in models without rapid citrate exhaustion.
