R-Lipoic Acid Inhibits Mammalian Pyruvate Dehydrogenase Kinase

• Published in: Free radical research 2004-10, Vol.38 (10), p.1083-1092
• Main Authors: Korotchkina, Lioubov G., Sidhu, Sukhdeep, Patel, Mulchand S.
• Format: Article
• Language: English
• Subjects: Acetyltransferases - metabolism; Binding Sites; Diabetes; Dihydrolipoyllysine-Residue Acetyltransferase; Glucose - metabolism; Humans; Lactic Acid - metabolism; Lipoic acid; Phosphorylation; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase - antagonists & inhibitors; Pyruvate Dehydrogenase (Lipoamide)-Phosphatase - metabolism; Pyruvate dehydrogenase complex; Pyruvate Dehydrogenase Complex - metabolism; Pyruvate dehydrogenase kinase isoenzymes; Pyruvate dehydrogenase phosphatase; Pyruvic Acid - metabolism; Thioctic Acid - pharmacology
• ISSN: 1071-5762; 1029-2470
• DOI: 10.1080/10715760400004168

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 ∼ 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.