NEBRASKA REDOX BIOLOGY CENTER EDUCATIONAL PORTAL

Nebraska Redox Biology Center Educational Portal


α-Lipoic Acid

α-Lipoic acid (LA) is a dithiol compound synthesized enzymatically in the mitochondria. Lipoic acid serve as essential cofactor for several redox reactions and is found in all domains of life. Lipoic acid is present in the cell in oxidized form with a ring-shaped intramolecular disulfide bond, an intermediate form with sulphur-conjugated substrate, and a reduced form that contains two sulfhydryls. Dihydrolipoamide dehydrogenase catalyzes regeneration of the oxidized form by reacting with NAD+ and formation of NADH. Eukaryotic lipoic acid is located exclusively in mitochondria sized de novo. α-Lipoic acid exist in form of R- and S- enantiomers and R- enantiomer is predominant in biological systems [ 1, 2, 3 ].

R and S enantiomers of Lipoic Acid.

In proteins, R-enantiomer of lipoic acid is covalently attached by amide linkage to the amino group of a lysine residue and naturally occur as lipoamide [ 1, 2, 3 ]. Vegetables and animal tissues contain low amounts of lipoic acid, which is present in the form of lipoyllysine. The most abundant plant sources of lipoic acid are spinach, broccoli and tomatoes, which contain 3.15 ± 1.11, 0.94 ± 0.25, and 0.56 ± 0.23 μg of lipoyllysine/g dry weightt respectively. The highest concentration of lipoyllysine in animal tissues was found in kidney, heart, and liver containing 2.64 ± 1.23, 1.51 ± 0.75, and 0.86 ± 0.33 μg of lipoyl-lysine/g dry weight, respectively [ 1, 2, 4 ]. Synthetic 1:1 mixture of R- and S-enantiomers is used as dietary supplement and therapeutic agent. There no upper limit for lipoic acid consumption has been established for human, however, safe levels for oral lipoic intake have been defined in animal models. Lipoic acid LD50 for dog is 400-500 mg/kg, mouse 500 mg/kg, cat 30 mg/kg and rat >2000 mg/kg. Several clinical trials used lipoic acid as oral supplement with up to 2400 mg/day or intravenous supplement in doses of 600 mg/day did not reported adverse effects versus placebo [ 2, 4, 5, 6 ].

The lipoic acid (LA) cofactor is covalently bound to protein via an amide bond (lipoamide) to the ε-amino group of a lysine in a conserved lipoylation domain. The oxidized form is ready for reaction with different substrates and forms an intermediate until the substrate is released and the reduced form with two sulfhydryls (dihydrolipoamide) is generated. Dihydrolipoamide dehydrogenase (DLD) catalyzes the reactivation of the cofactor by a redox reaction with NAD+ [ 1, ].

The redox activity of lipoic is mainly conferred by its dithiolane ring. The oxidized (Lipoic Acid) and reduced (Dihydrolipoic Acid or DHLA) a potent redox couple with standard reduction potential of -0.32 V. Reduced form of lipoic acid DHLA potent naturally occurring antioxidants. Both lipoic acid and DHLA are capable of scavenging a variety of reactive oxygen species [ 3, 7, 8, 9, 10, 11 ]. Lipoic acid and dihydrolipoic acid are involved in scavenging peroxynitrite, peroxyl radical and hypochlorous acid, while lipoic acid also scavenge singlet oxygen. However, reduced and oxidized forms of lipoic acid are not active against hydrogen peroxide [ 2, 12, 13, 14, 15, 16 ].

In addition, dihydrolipoic acid is involved in regeneration of vitamins C and E. [ 2, 8, 17 ].

In addition to reactive oxygen species scavengers function, both lipoic acid and dihydrolipoic acid are chelator redox active metals. Lipoic acid preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot bind Fe3+. dihydrolipoic acid forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+ [ 2, 18 ].

Octanoyl-ACP, produced in mitochondrial fatty acid synthesis chain, is used to synthesize protein-bound lipoic acid. The octanoyl moiety is transferred to a conserved lysine in the glycine cleavage H protein by an enzyme called octanoyl transferase. The protein-bound octanoic acid is then sulphurated twice at positions 6 and 8 by [4Fe-4S] iron-sulphur cluster containing lipoic acid synthetase. Sulphur at position 6 in lipoate is formed in astereoselective way resulting in R-enantiomer production. At final step lipoate residue is transferred to conserved lysine residues in the lipoic acid dependant proteins by lipoyl transferase [ 1, 19, 20, 21 ].

Lipoic acid (LA) synthesis in mitochondrial matrix includes mitochondrial fatty acid synthesis II (FAS II), octanoyl transfer to the glycine cleavage H protein, LA synthetase, and lipoyl transferase. Human genes are shown in bold; orthologs in Saccharomyces cerevisiae are shown in brackets. Genes indicated in red have been associated with human disease. The included enzymatic reactions are the following: (1) malonyl-coenzyme A synthetase (in yeast: acetyl-coenzyme A carboxylase); (2) malonyl-coenzyme A, acyl-carrier protein acyltransferase; (3) 3-oxoacyl-acyl-carrier-protein synthase; (4) 3-oxoacyl-acyl-carrier-protein reductase; (5) 3-hydroxyacyl-thioester dehydratase; (6) trans-2-enoyl-coenzyme A reductase; (7) octanoyl transferase; (8) lipoic acid synthetase; (9) lipoyl transferase. PPT 4'-phosphopantetheine, SAM S-adenosyl methionine, FeS [4Fe-4S] iron-sulphur cluster [ 1 ].

Lipoic acid is a covalently bound cofactor (in form of lipoate) essential for five redox reactions in humans. #945-ketoglutarate dehydrogenase and pyruvate dehydrogenase enzymes are involved in energy metabolism. α-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, Branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase and glycine cleavage system are involved in amino acid metabolism [ 1, 22, 23, 24 ].


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