lipoic acid lipoic acid lipoic acid (la), also known as α-lipoic acid, alpha-lipoic acid (ala) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ala is made in animals normally, and is essential for aerobic metabolism. it is also manufactured and is available as a dietary supplement in some countries where it is marketed as an antioxidant, and is available as a pharmaceutical drug in other countries. lipoate is the conjugate base of lipoic acid, and the most prevalent form of la under physiological conditions. only the (r)-(+)-enantiomer (rla) exists in nature and is essential for aerobic metabolism because rla is an essential cofactor of many enzyme complexes. lipoic acid names iupac name (r)-5-(1,2-dithiolan-3-yl)pentanoic acid other names α-lipoic acid; alpha lipoic acid; thioctic acid; 6,8-dithiooctanoic acid identifiers cas number 1077-28-7 (racemate) y1200-22-2 (r) y 3d model (jsmol) interactive image chebi chebi:30314 y chembl chembl134342 y chemspider 5886 y drugbank db00166 y echa infocard 100.012.793 iuphar/bps 4822 kegg c16241 y mesh lipoic+acid pubchem cid 6112 unii 73y7p0k73y (racemate) yvll71ebs9z (r) y comptox dashboard (epa) dtxsid7025508 inchi inchi=1s/c8h14o2s2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7h,1-6h2,(h,9,10)/t7-/m1/s1 ykey: agbqknbqesqnjd-ssdottswsa-n yinchi=1/c8h14o2s2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7h,1-6h2,(h,9,10)/t7-/m1/s1key: agbqknbqesqnjd-ssdottswbz smiles o=c(o)cccc1sscc1 properties chemical formula c8h14o2s2 molar mass 206.32 g·mol−1 appearance yellow needle-like crystals melting point 60–62 °c (140–144 °f; 333–335 k) solubility in water very slightly soluble(0.24 g/l) solubility in ethanol 50 mg/ml soluble pharmacology atc code a16ax01 (who) pharmacokinetics: bioavailability 30% (oral) related compounds related compounds lipoamideasparagusic acid except where otherwise noted, data are given for materials in their standard state (at 25 °c , 100 kpa). n verify (what is yn ?) infobox references physical and chemical properties lipoic acid (la), also known as α-lipoic acid, alpha-lipoic acid (ala), and thioctic acid is an organosulfur compound derived from octanoic acid. la contains two sulfur atoms (at c6 and c8) connected by a disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states. the carbon atom at c6 is chiral and the molecule exists as two enantiomers (r)-(+)-lipoic acid (rla) and (s)-(-)-lipoic acid (sla) and as a racemic mixture (r/s)-lipoic acid (r/s-la). la appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring. 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, a-ketoglutarate dehydrogenase, the glycine cleavage system, branched chain keto acid dehydrogenase, and the alpha-oxo(keto)adipate dehydrogenase. the first two are critical to the citric acid cycle. the gcs regulates glycine concentrations. 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 fatty acid biosynthesis in the form of octanoyl-acyl carrier protein. in eukaryotes, a second fatty acid biosynthetic pathway in mitochondria is used for this purpose. the octanoate is transferred as a thioester of acyl carrier protein from 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 (b7) and pantothenic acid (b5), lipoic acid enters cells through the smvt (sodium-dependent multivitamin transporter). 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. 2-oxoacid dehydrogenase transfer reactions occur by a similar mechanism in: the pyruvate dehydrogenase complex the α-ketoglutarate dehydrogenase or 2-oxoglutarate dehydrogenase complex the branched-chain oxoacid dehydrogenase (bcdh) complex the acetoin dehydrogenase complex. 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 (3-hydroxy-2-butanone) 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 (thf) 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 (prior to supplementation) 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 (r)-lipoyl-l-lysine are rapidly cleaved by serum lipoamidases, which release free (r)-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. chemical synthesis (r)-lipoic acid (rla, top) and (s)-lipoic acid (sla, down). a 1:1 mixture (racemate) of (r)- and (s)-lipoic acid is called (rs)-lipoic acid or (±)-lipoic acid (r/s-la). 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 (the nutritionally and therapeutically preferred form). 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. pharmacodynamics the mechanism and action of lipoic acid when supplied externally to an organism is controversial. lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. this effect is specific for rla. despite the strongly reducing milieu, la has been detected intracellularly in both oxidized and reduced forms. la is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of la. the relatively good scavenging activity of la toward hypochlorous acid (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to dhla. in cells, la is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of la and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper. this theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of dhla as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. although both dhla and la have been found inside cells after administration, most intracellular dhla probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins. recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. however, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects. all the disulfide forms of la (r/s-la, rla and sla) can be reduced to dhla although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. at least two cytosolic enzymes, glutathione reductase (gr) and thioredoxin reductase (trx1), and two mitochondrial enzymes, lipoamide dehydrogenase and thioredoxin reductase (trx2), reduce la. sla is stereoselectively reduced by cytosolic gr whereas trx1, trx2 and lipoamide dehydrogenase stereoselectively reduce rla. (r)-(+)-lipoic acid is enzymatically or chemically reduced to (r)-(-)-dihydrolipoic acid whereas (s)-(-)-lipoic acid is reduced to (s)-(+)-dihydrolipoic acid. dihydrolipoic acid (dhla) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions. rla may function