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Protein-Bound Alpha-Lipoic Acid

Enzyme Cofactor
R-LA is an essential cofactor for several mitochondrial enzyme complexes that catalyze critical reactions related to energy production and the catabolism (breakdown) of alpha-keto acids and amino acids (17). In each case, R-LA is covalently bound to a specific lysine residue in one of the proteins in the enzyme complex. The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-coenzyme A (CoA), an important substrate for energy production via the citric acid cycle. The alpha-ketoglutarate dehydrogenase complex catalyzes the conversion of alpha-ketoglutarate to succinyl CoA, another important citric acid cycle intermediate. The activity of the branched-chain ketoacid dehydrogenase complex results in the catabolism of the branched-chain amino acids, leucine, isoleucine and valine (18). The glycine cleavage system is a multi-enzyme complex that catalyzes the oxidation of glycine to form 5,10 methylene tetrahydrofolate, an important cofactor in nucleic acid synthesis (19).

Free Alpha-Lipoic Acid

When considering the biological activities of supplemental free LA, it is important to keep in mind the limited and transient nature of the increases in plasma and tissue LA (see Metabolism and Bioavailability above) (3).

Antioxidant Activities

Scavenging Reactive Oxygen and Nitrogen Species: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive compounds with the potential to damage DNA, proteins and lipids (fats) in cell membranes. Both LA and DHLA can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube [reviewed in (3)]. However, it is not clear whether LA acts directly to scavenge ROS and RNS in vivo. The highest tissue concentrations of free LA likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and glutathione. Moreover, free LA is rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Regeneration of Other Antioxidants: When an antioxidant scavenges a free radical, it becomes oxidized itself and is not able to scavenge additional ROS or RNS until it has been reduced. DHLA is a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including vitamin C and glutathione (20). DHLA may also reduce the oxidized form of alpha-tocopherol (the alpha-tocopheroxyl radical) directly or indirectly, by reducing the oxidized form of vitamin C (dehydroascorbate), which is able to reduce the alpha-tocopheroxyl radical (21). Coenzyme Q10 is an important component of the mitochondrial electron transport chain that also has antioxidant activity. DHLA can also reduce oxidized forms of coenzyme Q10 (22), which may also reduce the alpha-tocopheroxyl radical (23). Although DHLA has been found to regenerate oxidized antioxidants in the test tube, it is not known whether DHLA effectively regenerates other antioxidants under physiological conditions (3).

Metal Chelation: Redox-active metal ions, such as free iron and copper, can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals (24). Compounds that chelate (bind) free metal ions in a way that prevents them from generating free radicals offer promise in the treatment of neurodegenerative and other chronic diseases, in which metal-induced oxidative damage may play a role (25). Both LA and DHLA have been found to inhibit copper- and iron-mediated oxidative damage in the test tube (26, 27), and to inhibit excess iron and copper accumulation in animal models (28, 29).

Induction of Glutathione Synthesis: Glutathione is an important intracellular antioxidant that also plays a role in the detoxification and elimination of potential carcinogens and toxins. Studies in animals have found that glutathione synthesis and tissue glutathione levels are significantly lower in aged animals than in younger animals, leading to decreased ability of aged animals to respond to oxidative stress or toxin exposure (30). LA has been found to increase glutathione synthesis in cultured cells and in the tissues of aged animals fed LA. Recent research suggests that LA may increase glutathione synthesis in aged animals by increasing the expression of gamma-glutamylcysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis (31) and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis (32).

Adverse Effects

In general, LA supplementation has been found to have few serious side effects. Intravenous administration of racemic LA at doses of 600 mg/day for 3 weeks (53) and oral racemic LA at doses as high as 1800 mg/day for 6 months (56) and 1200 mg/day for 2 years (55) did not result in serious adverse effects when used to treat diabetic peripheral neuropathy. Two minor anaphylactoid reactions and one severe anaphylactic reaction, including laryngospasm, were reported after intravenous LA administration (40). The most frequently reported side effects to oral LA supplementation are allergic reactions affecting the skin, including rashes, hives and itching. Gastrointestinal symptoms, including abdominal pain, nausea, vomiting and diarrhea have also been reported. Malodorous urine has also been noted by people taking 1200 mg/day of LA orally (60).