12) http:/// pubmed/15512796
Free Radic Res. 2004 Oct;38(10):1083-92. R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase. Korotchkina LG1, Sidhu S, Patel MS. 1Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA.
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 pyruvate dehydrogenase complex (PDC) activity . This finding provides a possible mechanism for a glucose (and lactate) lowering effect of R-lipoic acid in diabetic subjects.
PKB/Akt-dependent signaling : In addition to insulin signaling, phosphorylation and dephosphorylation of other cell-signaling molecules affect a variety of cellular processes, including metabolism , stress responses, proliferation , and survival (3) . One such molecule is protein kinase B, also known as Akt (PKB/Akt). LA has been found to activate PKB/Akt-dependent signaling in vitro (37 , 40-42) and in vivo (42) , inhibit apoptosis in cultured hepatocytes (37) , and increase survival of cultured neurons (40) . LA has also been shown to improve nitric oxide -dependent vasodilation in aged rats by increasing PKB/Akt-dependent phosphorylation of endothelial nitric oxide synthase (eNOS), which increases eNOS- catalyzed production of nitric oxide (43) .