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PubMed2005

Mechanistic investigations of lipoic acid biosynthesis in Escherichia coli: both sulfur atoms in lipoic acid are contributed by the same lipoyl synthase polypeptide.

Lipoyl synthase catalyzes the final step in the de novo biosynthesis of the lipoyl cofactor, which is the insertion of two sulfur atoms into an octanoyl chain that is bound in an amide linkage to a conserved lysine on a lipoyl-accepting protein. We show herein that the sulfur atoms in the lipoyl cofactor are derived from lipoyl synthase itself, and that each lipoyl synthase polypeptide contributes both of the sulfur atoms to the intact cofactor.

Bacterial Proteins↗
PubMed1987

Amino acid sequence surrounding the lipoic acid cofactor of bovine kidney 2-oxoglutarate dehydrogenase complex.

The 2-oxoglutarate dehydrogenase complex was succinylated using 2-oxo[5-14C]glutarate in the presence of N-ethylmaleimide to label the lipoic acid cofactor of the transuccinylase (E2) component. Following peptic digestion, 14C-lipoate-containing peptides were purified and subjected to automated Edman degradation and amino acid analysis. The amino acid sequence surrounding the lipoyllysine residue is reported.

Amino Acid Sequence↗
PubMed1997

Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production.

The function of acyl carrier protein (ACP) in mitochondria isolated from pea leaves has been investigated. When pea leaf mitochondria were labeled with [2-14C] malonic acid in vitro, radioactivity was incorporated into fatty acids, and, simultaneously, ACP was acylated. [1-14C]Acetate was much less effective as a precursor for fatty acid synthesis, suggesting that mitochondria do not possess acetyl-CoA carboxylase. The incorporation of radioactivity from [2-14C]malonate into fatty acids and the labeling of ACP were inhibited by cerulenin and required ATP and Mg2+. These findings indicate that plant mitochondria contain not only ACP, but all enzymes required for de novo fatty acid synthesis. Over 30% of the radioactive products from pea mitochondria labeled with [2-14C]malonate were recovered in H protein, which is a subunit of glycine decarboxylase and contains lipoic acid as an essential constituent. In similar experiments, the H protein of Neurospora mitochondria was also labeled by [2-14C]malonate. The labeling of pea H protein was inhibited by addition of cerulenin into the assay medium. Together, these findings indicate that ACP is involved in the de novo synthesis of fatty acids in plant mitochondria and that a major function of this pathway is production of lipoic acid precursors.

Acyl Carrier Protein↗
PubMed1996

Reduction of lipoic acid by lipoamide dehydrogenase.

Racemic lipoic acid is therapeutically applied in pathologies in which free radicals are involved. The in vivo reduction of lipoic acid may play an essential role in its antioxidant effect. It was found that mitochondrial lipoamide dehydrogenase (LipDH, EC 1.8.1.4.) reduces the R-enantiomer 28 times faster than the S-enantiomer of lipoic acid. Moreover, it was observed that the metabolites of lipoic acid, bisnor-, tetranor-, and beta-lipoic acid are poor substrates of LipDH. S-lipoic acid inhibits the reduction of the R enantiomer only at relatively high concentrations. The reduction of R-lipoic acid by mitochondria-rich tissues may proceed smoothly, even if the racemic mixture is applied. This is of importance in elucidating the molecular mechanism of the pharmacotherapeutic effect of lipoic acid.

Animals↗
PubMed2000

Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats.

BACKGROUND AND OBJECTIVES: In spontaneously hypertensive rats (SHRs), excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether a dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound that is known to increase tissue cysteine and glutathione, can lower blood pressure and normalize associated biochemical and histopathological changes in SHRs. METHODS AND RESULTS: Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the Wistar- Kyoto (WKY) rat control group and the SHR control group were given a normal diet, and the SHR-lipoic acid group was given a diet supplemented with lipoic acid (500 mg/kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared with WKY rat controls and the SHR lipoic acid group. SHR controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. CONCLUSIONS: Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.

Aldehydes↗
PubMed1999

Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy.

AIMS: To evaluate the efficacy and safety of short-term oral treatment with the antioxidant thioctic acid (TA) on neuropathic symptoms and deficits in patients with Type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: Patients were randomly assigned to oral treatment with 600 mg of TA t.i.d. (n = 12) or placebo (n = 12) for 3 weeks. Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) in the feet were scored at weekly intervals and summarized as a Total Symptom Score (TSS). The Hamburg Pain Adjective List (HPAL) and the Neuropathy Disability Score (NDS) were assessed at baseline and day 19. RESULTS: At baseline the TSS, HPAL, and NDS were not significantly different between the groups. The TSS in the foot decreased from baseline to day 19 by -3.75 +/- 1.88 points (-47%) in the TA group and by -1.94 +/- 1.50 points (-24%) in the placebo group (P= 0.021 for TA vs. placebo). The total HPAL score decreased from baseline to day 19 by -2.20 +/- 1.65 points (-60%) in the TA group and by -0.96 +/- 1.32 points (-29%) in the placebo group (P = 0.072 for TA vs. placebo). The NDS decreased by -0.27 +/- 0.47 points in the TA group, whereas it slightly increased by +0.18 +/- 0.4 points in the placebo group (P = 0.025 for TA vs. placebo). No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These preliminary findings indicate that oral treatment with 600 mg of TA t.i.d. for 3 weeks may improve symptoms and deficits resulting from polyneuropathy in Type 2 diabetic patients, without causing significant adverse reactions.

Aged↗
PubMed1976

Stability of injection solutions of vitamin B1. Part 2: Influence of lipoic acid.

DL-alpha-Lipoic acid at low concentrations increases the stability of thiamine hydrochloride solutions, however, at higher concentrations the degradation rate of the vitamin is enhanced. The optimum concentration of lipoic acid at which its stabilizing efficiency is maximum is shifted on the addition of 20 ppm of copper, from 0.5 to 1.0 mmole/1, indicating that this optimum concentration is dependent on heavy metal ions concentration in the solution. In the presence of copper, the degradation rate of the vitamin in solutions containing lipoic acid at concentrations higher than its optimum concentration is lower than that in corresponding solutions in the absence of added copper. On the other hand, below the optimum concentration, the degradation rate of thiamine hydrochloride solutions in the absence of copper is lower than that of the corresponding solutions to which 20 ppm copper have been added. This indicates that the presence of either free copper ions or an excess of lipoic acid is deleterious to the stability of the vitamin.

Copper↗
PubMed2000

Dietary lipoic acid supplementation prevents fructose-induced hypertension in rats.

BACKGROUND AND AIMS: In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, alter membrane Ca2+ channels and increase cytosolic free calcium and blood pressure. The thiol compound N-acetyl cysteine prevents such hypertension by binding these aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of this work was to investigate whether dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound known to increase cysteine and glutathione, prevents this hypertension and its associated biochemical and histopathological changes. METHODS AND RESULTS: Starting at seven weeks of age, animals were divided into three groups of six animals each and treated as follows: control (normal diet and normal drinking water); fructose (normal diet and 4% fructose in drinking water); fructose + lipoic acid (diet supplemented with lipoic acid 500 mg/kg feed and 4% fructose in drinking water). After 14 weeks, systolic blood pressure, platelet [Ca2+]i, plasma glucose and insulin and kidney and aortic aldehyde conjugates were significantly higher in the fructose group. These also displayed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. CONCLUSION: Dietary alpha-lipoic acid supplementation in fructose-treated WKY rats may prevent their increase in systolic blood pressure by normalizing cytosolic [Ca2+], blood glucose and insulin, kidney and aortic aldehyde conjugates and preventing adverse renal vascular changes.

Aldehydes↗
PubMed2002

Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells.

Alpha-lipoic acid, which becomes a powerful antioxidant in its reduced form, has been suggested as a dietary supplement to treat diseases associated with excessive oxidant stress. Because the vascular endothelium is dysfunctional in many of these conditions, we studied the uptake, reduction, and antioxidant effects of alpha-lipoic acid in cultured human endothelial cells (EA.hy926). Using a new assay for dihydrolipoic acid, we found that EA.hy926 cells rapidly take up and reduce alpha-lipoic acid to dihydrolipoic acid, most of which is released into the incubation medium. Nonetheless, the cells maintain dihydrolipoic acid following overnight culture, probably by recycling it from alpha-lipoic acid. Acute reduction of alpha-lipoic acid activates the pentose phosphate cycle and consumes nicotinamide adenine dinucleotide phosphate (NADPH). Lysates of EA.hy926 cells reduce alpha-lipoic acid using both NADPH and nicotinamide adenine dinucleotide (NADH) as electron donors, although NADPH-dependent reduction is about twice that due to NADH. NADPH-dependent alpha-lipoic acid reduction is mostly due to thioredoxin reductase. Pre-incubation of cells with alpha-lipoic acid increases their capacity to reduce extracellular ferricyanide, to recycle intracellular dehydroascorbic acid to ascorbate, to decrease reactive oxygen species generated by redox cycling of menadione, and to generate nitric oxide. These results show that alpha-lipoic acid enhances both the antioxidant defenses and the function of endothelial cells.

Antioxidants↗
PubMed2002

Capillary zone electrophoresis study of cyclodextrin--lipoic acid host-guest interaction.

Lipoic acid is a naturally occurring compound which is being widely investigated for its therapeutic effects in the treatment or prevention of a variety of diseases associated with oxidative injury, particularly diabetes. The diversity of therapeutic applications of lipoic acid requires an appropriate formulation to control its bioavailability, site-targeting delivery and to overcome its inherent chemical instability. In this regard, cyclodextrins (CDs) are ideally suitable due to their well-documented ability to include in their cavity proper guest molecules and protect them from physical or chemical damages. Lipoic acid forms 1:1 inclusion complexes with betaCD as shown in a previous report of an extended investigation that also indicated the suitability of capillary zone electrophoresis (CZE) for the study of such host-guest interactions. In view of these possible applications, we extended the CZE analysis to determine the strength of binding, in a pH 9 phosphate buffer, of lipoic acid with other CD derivatives such as alphaCD, gammaCD and the alkylated derivatives of betaCD, namely (2-hydroxypropyl)-beta-CD (HPbetaCD), and heptakis(2,3,6-tri-O-methyl)-beta-CD (TMbetaCD). Once established that the easily available betaCD is the most suitable receptor for lipoic acid, we set up and here describe a simple and reliable procedure for the quantitative determination of lipoic acid in commercial dietary supplement tablets containing also other active substances and excipients.

Antioxidants↗
PubMed2005

[Lipoic acid: characteristics and therapeutic application].

Lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA, are present in all prokaryotic and eukaryotic cells. Lipoic acid was once considered a vitamin, but now it is commonly accepted that it can be synthesized de novo in human cells. LA has long been known as a coenzyme of multienzymatic complexes catalyzing the decarboxylation of alpha-ketoacids, but the present investigations are focused on its antioxidative properties. Both LA and DHLA have proved to be potent free radicals scavengers and metal chelators. They are also responsible for the regeneration of active forms of other cellular antioxidants, including vitamins C and E. Moreover, lipoic acid is involved in the regulation of carbohydrate and lipid metabolism. LA is easily absorbed from the gastrointestinal tract, is able to cross the blood-brain barrier, and does not exhibit any serious side effects. All these features make lipoic acid a very promising drug. Nowadays, this compound is used in the treatment of diabetic neuropathy, fungi, and metal poisoning, as well as in liver disorders. The application of lipoic acid in treating other diseases, including hypertension and autoimmunological disorders, needs careful evaluation.

Animals↗
PubMedDate not supplied

[Pharmacokinetics of preparations of lipoic acid and their effect on ATP synthesis, processes of microsomal and cytosol oxidation in hepatocytes in liver damage in man].

The features of the pharmacokinetics of preparations of alpha-lipoic acid (lipoic acid, thioctacide) as compared with their pharmacodynamic effects were studied in 125 patients with chronic diffuse diseases of the liver of viral and alcohol etiology. After a single administration of the preparations, the authors found an elevation of the maximal blood concentrations and an increase of alpha-lipoic acid elimination half-life in patients with liver cirrhosis as compared with chronic hepatitis patients. During the replacement therapy and elimination of alpha-lipoic acid deficiency by using the preparations containing lipoic acid, there is commonly an increase ATP content, an elevation of functioning mass of hepatocytes and activation of liver detoxifying function according to the data of the tests of galactose cytosol oxidation, microsomal oxidation of antipyrine and conjugation of bilirubin.

Adenosine Triphosphate↗