What question did this study set out to answer?

Determine the biochemical mechanism by which dichloroacetate and related halogenated carboxylic acids stimulate pyruvate dehydrogenase activity and influence whole-body carbohydrate metabolism.

September 1, 1974Biochemical JournalOpen Access

Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids

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Authors

SWS WhitehouseHoward Hughes Medical Institute RCRonald H. CooperMadigan Army Medical Center PRPhilip J. RandleUniversity of Oxford

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Implication

Laboratory study demonstrates dichloroacetate activates pyruvate dehydrogenase by inhibiting its kinase in rodent tissues, highlighting mechanisms driving lactate and glucose reduction.

Key Points

Determine the biochemical mechanism by which dichloroacetate and related halogenated carboxylic acids stimulate pyruvate dehydrogenase activity and influence whole-body carbohydrate metabolism.
Assayed kinase, phosphatase, and direct catalytic activities of purified pig and rat heart pyruvate dehydrogenase complexes in the presence of halogenated carboxylic acids.
Measured the proportion of active, dephosphorylated enzyme in isolated mitochondria and intact tissue preparations, including perfused rat heart, diaphragm, and epididymal fat pads.
Injected dichloroacetate into overnight-starved rats to track in vivo enzyme activation across major organs and monitor blood concentrations of lactate, glucose, and glycerol over 120 minutes.
Dichloroacetate, related chloroacetates, and chloropropionates non-competitively inhibited pyruvate dehydrogenase kinase with respect to ATP (50% inhibition at approx. 100 µM) without altering phosphatase activity or basal catalytic function.
Dichloroacetate shifted pyruvate dehydrogenase toward its active dephosphorylated state in isolated mitochondria, perfused tissues, and starved rat organs within 60 minutes.
In vivo administration caused blood lactate to drop within 15 minutes to a minimum at 60 minutes, followed by a decline in blood glucose beginning at 90 minutes with a minimum at 120 minutes.

Cite This Study

Whitehouse et al. (1974) studied this question.

synapsesocial.com/papers/6a1bc64dbc71fb1015a8f3b1 https://doi.org/10.1042/bj1410761

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Implication

Laboratory study demonstrates dichloroacetate activates pyruvate dehydrogenase by inhibiting its kinase in rodent tissues, highlighting mechanisms driving lactate and glucose reduction.

Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids

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Implication

Key Points

Cite This Study

Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids

Discussion

Member takes

Implication

Key Points

Cite This Study

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