R-Lipoic Acid Inhibits Mammalian Pyruvate Dehydrogenase Kinase

Abstract

The four pyruvate dehydrogenase kinase (PDK) and two pyruvate dehydrogenase phosphatase (PDP) isoenzymes that are present in mammalian tissues regulate activity of the pyruvate dehydrogenase complex (PDC) by phosphorylation/dephosphorylation of its pyruvate dehydrogenase (E1) component. The effect of lipoic acids on the activity of PDKs and PDPs was investigated in purified proteins system. R-lipoic acid, S-lipoic acid and R-dihydrolipoic acid did not significantly affect activities of PDPs and at the same time inhibited PDKs to different extents (PDK1>PDK4 approximately PDK2>PDK3 for R-LA). Since lipoic acids inhibited PDKs activity both when reconstituted in PDC and in the presence of E1 alone, dissociation of PDK from the lipoyl domains of dihydrolipoamide acetyltransferase in the presence of lipoic acids is not a likely explanation for inhibition. The activity of PDK1 towards phosphorylation sites 1, 2 and 3 of E1 was decreased to the same extent in the presence of R-lipoic acid, thus excluding protection of the E1 active site by lipoic acid from phosphorylation. R-lipoic acid inhibited autophosphorylation of PDK2 indicating that it exerted its effect on PDKs directly. Inhibition of PDK1 by R-lipoic acid was not altered by ADP but was decreased in the presence of pyruvate which itself inhibits PDKs. An inhibitory effect of lipoic acid on PDKs would result in less phosphorylation of E1 and hence increased PDC activity. This finding provides a possible mechanism for a glucose (and lactate) lowering effect of R-lipoic acid in diabetic subjects.

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

“…Inactivation of the E1 component of the PDC complex occurs when PDHK phosphorylates three serine residues on E1 (ser264, ser271 and ser203) (47). It has been shown that lipoic acid restores the activity of PDH through the inhibition of PDHK (26).…”

“…Furthermore, Koukourakis et al have reported either a significant reduction of PDH protein levels or a significant increase of PDH kinase 1 levels (PDHK1) in human resected lung cancer tissues (20,25). We chose to target restoration of PDH activity through the use of alpha lipoic acid (ALA), also a known inhibitor of PDHK1 (26).…”

The pyruvate carboxylase-pyruvate dehydrogenase axis in islet pyruvate metabolism: Going round in circles?

“…103) and there may be an involvement of PKCδ in acute activation of PDHK2 by its phosphorylation. 104 In heart, translocation of PKCδ to the mitochondria can prevent reactivation and/or promote continued PDC inactivation by phosphorylation and activation of PDHK2.…”

Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo

“…13 Additionally LPA can inhibit pyruvate dehydrogenase kinase, thus increasing the activity of the pyruvate dehydrogenase complex. 14,15 Similarly, efficacy of dichloroacetate (DCA) in cancer therapy most probably also results from inhibition of mitochondrial pyruvate dehydrogenase kinase hence shifting cell metabolism toward oxidative turnover. 16,17 DCA has been reported to induce apoptosis, probably caused by enhanced measurement over 80 h of electrical impedance of cells revealed that LPA significantly reduces the cell viability/proliferation in all four cell lines analyzed both at 1 and 5 mM.…”