Inhibition of the Activity of the PDHC by (R)- or (S)-Lipoic Acid

Yeah, this article shows that either free (R)-lipoic acid or free (S)-lipoic acid can inhibit the overall activity of the pyruvate dehydrogenase complex. That's not that surprising, because some drugs used to lower blood glucose levels or increase insulin sensitivity (usually both effects) are thought to work by either inhibiting AMP-activating protein kinase or inhibiting mitochondrial function more directly. The cells compensate for the increased AMP/ATP ratio by upregulating glucose transport, and the extra glucose uptake compensates for the effect of the inhibitor. The increased glucose transport could sort of compensate for the inhibition of the activity of the PDHC, but what would the mechanism for that compensation be? Maladaptive mitochondrial proliferation? Inhibition of the PDHC activity wouldn't be expected to be especially desirable, under many sets of circumstances.

This article says acetaldehyde inhibits the overall PDHC activity (it doesn't mean the other article I mentioned is "wrong," and the two groups of researchers may have been using different conditions) by competing with lipoic acid enantiomers for binding to an inhibitory site. The same substance could potentially act as either an inhibitor or activator, depending on the conditions or any number of factors. But that's part of the issue. There are some unknowns with lipoic acid. The article says (S)-lipoic acid is the more potent inhibitor, which is the effect that could reasonably be expected with an unnatural enantiomer like (S)-lipoic acid.

http://www.ncbi.nlm.nih.gov/pubmed/7669066 (Loffelhardt et al., 1995)