Lipoic acid
Lipoic acid, also known as α-lipoic acid, alpha-lipoic acid and thioctic acid, is an organosulfur compound derived from caprylic acid. ALA, which is made in animals normally, is essential for aerobic metabolism. It is also available as a dietary supplement or pharmaceutical drug in some countries. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Only the --enantiomer exists in nature. RLA is an essential cofactor of many processes.
Physical and chemical properties
Lipoic acid contains two sulfur atoms connected by a disulfide bond in the 1,2-dithiolane ring. It also carries a carboxylic acid group. It is considered to be oxidized relative to its acyclic relative dihydrolipoic acid, in which each sulfur exists as a thiol. It is a yellow solid.--lipoic acid occurs naturally, but --lipoic acid has been synthesized.
For use in dietary supplement materials and compounding pharmacies, the USP established an official monograph for R/S-LA.
Biological function
Lipoic acid is a cofactor for five enzymes or classes of enzymes: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, the glycine cleavage system, branched-chain alpha-keto acid dehydrogenase, and the α-oxoadipate dehydrogenase. The first two are critical to the citric acid cycle. The GCS regulates glycine concentrations.HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are targets of the reduced form of -lipoic acid.
Biosynthesis and attachment
Most endogenously produced RLA are not "free" because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme's lipoyl domains.The precursor to lipoic acid, octanoic acid, is made via mitochondrial fatty acid biosynthesis in the form of octanoyl-acyl carrier protein. The octanoate is transferred as a thioester of acyl carrier protein from mitochondrial fatty acid biosynthesis to an amide of the lipoyl domain protein by an enzyme called an octanoyltransferase. Two hydrogens of octanoate are replaced with sulfur groups via a radical SAM mechanism, by lipoyl synthase. As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase. Free lipoate can be used by some organisms as an enzyme called lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.
Cellular transport
Along with sodium and the vitamins biotin and pantothenic acid, lipoic acid enters cells through the SMVT. Each of the compounds transported by the SMVT is competitive with the others. For example research has shown that increasing intake of lipoic acid or pantothenic acid reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.Enzymatic activity
Lipoic acid is a cofactor for at least five enzyme systems. Two of these are in the citric acid cycle through which many organisms turn nutrients into energy. Lipoylated enzymes have lipoic acid attached to them covalently. The lipoyl group transfers acyl groups in 2-oxoacid dehydrogenase complexes, and methylamine group in the glycine cleavage complex or glycine dehydrogenase.Lipoic acid is the cofactor of the following enzymes in humans:
| EC-number | Enzyme | Gene | Multienzyme complex | Role of the complex |
| EC | dihydrolipoyl transacetylase | DLAT | pyruvate dehydrogenase complex | Connection of glycolysis with the citric acid cycle |
| EC | dihydrolipoyl succinyltransferase | DLST | oxoglutarate dehydrogenase complex | Citric acid cycle enzyme |
| EC | dihydrolipoyl succinyltransferase | DLST | 2-oxoadipate dehydrogenase complex | Lysine, tryptophan and hydroxylysine degradation |
| EC | dihydrolipoyl transacylase | DBT | branched-chain α-ketoacid dehydrogenase complex | Leucine, isoleucine and valine degradation |
| H-protein | GCSH | glycine cleavage system | Glycine and serine metabolism, folate metabolism |
The most-studied of these is the pyruvate dehydrogenase complex. These complexes have three central subunits: E1-3, which are the decarboxylase, lipoyl transferase, and dihydrolipoamide dehydrogenase, respectively. These complexes have a central E2 core and the other subunits surround this core to form the complex. In the gap between these two subunits, the lipoyl domain ferries intermediates between the active sites. The lipoyl domain itself is attached by a flexible linker to the E2 core and the number of lipoyl domains varies from one to three for a given organism. The number of domains has been experimentally varied and seems to have little effect on growth until over nine are added, although more than three decreased activity of the complex.
Lipoic acid serves as co-factor to the acetoin dehydrogenase complex catalyzing the conversion of acetoin to acetaldehyde and acetyl coenzyme A.
The glycine cleavage system differs from the other complexes, and has a different nomenclature. In this system, the H protein is a free lipoyl domain with additional helices, the L protein is a dihydrolipoamide dehydrogenase, the P protein is the decarboxylase, and the T protein transfers the methylamine from lipoate to tetrahydrofolate yielding methylene-THF and ammonia. Methylene-THF is then used by serine hydroxymethyltransferase to synthesize serine from glycine. This system is part of plant photorespiration.
Biological sources and degradation
Lipoic acid is present in many foods in which it is bound to lysine in proteins, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract. Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. In addition, the amount of lipoic acid present in dietary sources is low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid. As a result, all lipoic acid available as a supplement is chemically synthesized.Baseline levels of RLA and R-DHLA have not been detected in human plasma. RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using subtilisin and alcalase, respectively.
Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-L-lysine amide bond. Both synthetic lipoamide and -lipoyl-L-lysine are rapidly cleaved by serum lipoamidases, which release free -lipoic acid and either L-lysine or ammonia. Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine.
Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals. Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice. Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized. Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.
Diseases
Combined malonic and methylmalonic aciduria (CMAMMA)
In the metabolic disease combined malonic and methylmalonic aciduria due to ACSF3 deficiency, mitochondrial fatty acid synthesis, which is the precursor reaction of lipoic acid biosynthesis, is impaired. The result is a reduced lipoylation degree of important mitochondrial enzymes, such as pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex. Supplementation with lipoic acid does not restore mitochondrial function.Chemical synthesis
SLA did not exist prior to chemical synthesis in 1952. SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent. The first synthetic procedures appeared for RLA and SLA in the mid-1950s. Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both classical resolution and asymmetric synthesis and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by Degussa. Although RLA is favored nutritionally due to its "vitamin-like" role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both stereospecific and non-stereospecific reactions are known to occur in vivo and contribute to the mechanisms of action, but evidence to date indicates RLA may be the eutomer.Pharmacology
Pharmacokinetics
A 2007 human pharmacokinetic study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form. Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.The various forms of LA are not bioequivalent. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.
The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.