Lipoic acid
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	1200-22-2 Y
PubChem	6112
ChemSpider	5886 Y
DrugBank	DB00166
KEGG	C16241 Y
MeSH	Lipoic+acid
ChEBI	CHEBI:30314 Y
ChEMBL	CHEMBL134342 Y
ATC code	A16AX01
Jmol-3D images	Image 1
SMILES O=C(O)CCCC[C@H]1SSCC1
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 Y Key: AGBQKNBQESQNJD-SSDOTTSWSA-N Y InChI=1/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1 Key: AGBQKNBQESQNJD-SSDOTTSWBZ
Properties
Molecular formula	C8H14O2S2
Molar mass	206.33 g/mol
Appearance	yellow needle-like crystals
Solubility in water	soluble in ethanol, sodium salt is soluble in water
Pharmacology
Bioavailability	30% (oral)[1]
Related compounds
Related compounds	Lipoamide Asparagusic acid
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Lipoic acid (LA), also known as α-lipoic acid^[2] and alpha lipoic acid (ALA)^[3] is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms (at C6 and C8) attached 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). Only the R-(+)-enantiomer exists in nature and is an essential cofactor of four mitochondrial enzyme complexes.^[4] Endogenously synthesized RLA is essential for life and aerobic metabolism. Both RLA and R/S-LA are available as over-the-counter nutritional supplements and have been used nutritionally and clinically since the 1950s for various diseases and conditions. LA appears physically as a yellow solid and structurally contains a terminal carboxylic acid and a terminal dithiolane ring.

The relationship between endogenously synthesized (enzyme–bound) RLA and administered “free” RLA or R/S-LA has not been fully characterized but “free” plasma and cellular levels increase and decrease rapidly after oral consumption or intravenous injections. "Lipoate" is the conjugate base of lipoic acid, and the most prevalent form of LA under physiologic conditions. Although the intracellular environment is strongly reducing, both free LA and its reduced form, dihydrolipoic acid (DHLA), have been detected in cells after administration of LA. Most endogenously produced RLA is 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. One of the most studied roles of RLA is as a cofactor of the pyruvate dehydrogenase complex (PDC or PDHC), though it is a cofactor in other enzymatic systems as well (described below).

Biosynthesis and attachment[link]

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.^[5][6] The octanoate is transferred from a thioester of acyl carrier protein to an amide of the lipoyl domain by an octanoyltransferase. The sulfur centers are inserted into the 6th and 8th carbons of octanoate via the a radical s-adenosyl methionine mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide.^[7] As a result, lipoic acid is synthesized on the lipoyl domain and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.^[8] Free lipoate can be attached to the lipoyl domain by the enzyme lipoate protein ligase. The ligase activity of this enzyme requires ATP. Lipoate protein ligases proceed via an enzyme bound lipoyl adenylate intermediate.^[9]

Lipoic acid-dependent complexes[link]

2-OADH transfer reactions occur by a similar mechanism in the PDH complex, 2-oxoglutarate dehydrogenase (OGDH) complex, branched chain oxoacid dehydrogenase (BCDH) complex, and acetoin dehydrogenase (ADH) complex. The most studied of these is the PDH 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.^[10][11] The geometry of the PDH E2 core is cubic in Gram-negative bacteria or dodecahedral in Eukaryotes and Gram-positive bacteria. Interestingly the 2-OGDH and BCDH geometry is always cubic.^[12] 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.^[13] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.^[14]

Endogenous (enzyme-bound) R-lipoate also participates in transfer of acyl groups in the α-keto-glutarate dehydrogenase complex (KDHC or OGDC) and the branched-chain oxo acid dehydrogenase complex (BCOADC). RLA transfers a methylamine group in the glycine cleavage complex (GCV). RLA serves as co-factor to the acetoin dehydrogenase complex (ADC) catalyzing the conversion of acetoin (3-hydroxy-2-butanone) to acetaldehyde and acetyl coenzyme A, in some bacteria, allowing acetoin to be used as the sole carbon source.

The Glycine cleavage system differs from the other complexes, and has a different nomenclature. In this complex 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 (SHMT) to synthesize serine from glycine. This system is used by many organisms and plays a crucial role in the photosynthetic carbon cycle.^[15]

Biological sources and degradation[link]

Lipoic acid is found in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.^[16] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. Additionally, the amount of lipoic acid present is very 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.^[17] 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.^[18] 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.^[19][20][21] It has not been determined whether pre-supplementation levels of RLA derive from food sources, mitochondrial turnover and salvaging or from gut microbes but low levels have been correlated to a variety of disease states.^{[22][23][24][25]}

Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the R-lipoic acid-L-lysine amide bond.^[26] 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 into the bloodstream.^{[24][27][27][28][29][30]} It has recently been questioned whether or not food sources of RLA provide any measurable benefit nutritionally or therapeutically due to the very low concentrations present.^[31] Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiologic conditions. Most endogenous RLA is not "free" because octanaote is attached to the enzyme complexes that use it via LipA. The sulfur atoms derive from the amino acid L-cysteine and add asymmetrically to octanoate by lipoate synthase, thus generating the chiral center at C6.^[32] Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles.^[33][34] It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2).^[35]

Pharmacology and medical uses of free lipoic acid[link]

Today, R/S-LA and RLA are widely available as over-the-counter nutritional supplements in the United States in the form of capsules, tablets and aqueous liquids, and have been branded as antioxidants. This label has recently been challenged.^[2] In Japan, LA is marketed primarily as a "weight loss" and "energy" supplement. The relationships between supplemental doses and therapeutic doses have not been clearly defined. Because lipoic acid is not an essential nutrient, no Recommended Daily Allowance (RDA) has been established.

For use in dietary supplement materials and compounding pharmacies, the USP has established an official monograph for racemic R/S-LA.^[36]

Possible beneficial effects[link]

Lipoic acid has been the subject of numerous research studies and clinical trials:

• Prevent organ dysfunction^[37]

• Reduce endothelial dysfunction and improve albuminuria^[38][39]

• Treat or prevent cardiovascular disease^[40]

• Accelerate chronic wound healing^[41]

• Reduce levels of ADMA in diabetic end-stage renal disease patients on hemodialysis^[42]

• Management of burning mouth syndrome^[43][44][45]

• Reduce iron overload^[46]

• Treat metabolic syndrome^[47][48][49]

• Improve or prevent age-related cognitive dysfunction^[50][51]

• Prevent or slow the progression of Alzheimer’s Disease^[52][53][54]

• Prevent erectile dysfunction (animal models but anecdotally applies to humans as well)^[55][56]

• Prevent migraines^[57]

• Treat multiple sclerosis^[58][59][60]

• Treat chronic diseases associated with oxidative stress^[61]

• Reduce inflammation^[62]

• Inhibit advanced glycation end products (AGE)^[63]

• Treat peripheral artery disease.^[64]

RLA is a classic example of an orthomolecular nutrient, in the original sense of Linus Pauling. Due to the low cost and ease of manufacturing R/S-LA relative to RLA, as well as early successes in treatments, the racemic form was more widely used nutritionally and clinically in Europe and Japan, despite the early recognition that the various forms of LA were not bioequivalent.^[65] The original rationale for using R/S-lipoic acid (LA) as a nutritional supplement was that endogenous RLA was known to have biochemical properties like a B-vitamin (acting as a substrate or cofactor essential for enzyme function). It was also recognized that lower endogenous concentrations of RLA were found in tissues of humans with various diseases, and lower levels of RLA were found in the 24 hour urine of patients with various diseases than in healthy subjects.^{[23][24][25][66][67]} Injections of R/S-LA as low as 10–25 mg normalized daily urinary output and, in many cases, improved patient health. When it was demonstrated that mammals have the genes to endogenously synthesize RLA, it lost vitamin status, but is today considered to be a “conditionally essential nutrient”.^[68] The exact mechanisms of how RLA levels decline with age and in various progressive diseases is unknown. In addition, microbial assays used to quantify LA were essentially stereospecific for RLA (100% active for RLA, 0% activity for SLA), so it was believed SLA was essentially inert or of very low biological activity. This was proven false by Gal, who demonstrated stereospecific toxicity of the S-enantiomer in thiamine-deficient rats.^[69][70]

Several papers found RLA and acetyl carnitine reversed age-related markers in old rats to youthful levels.^{[71][72][73][74][75][76][77]}

RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin, sulphoraphane, resveratrol, and other nutritional substances that induce phase II detoxification enzymes, thus acting as cytoprotective agents.^[78][79] This stress response indirectly improves the antioxidant capacity of the cell.^[2]

A recent human pharmacokinetic study of 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.^[80] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.^[80]

Antioxidant and prooxidant effects of lipoic acid[link]

All of 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.^{[81][82][83][84][85][86][87]} Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.^[88]

The cytosolic and mitochondrial redox state is maintained in a reduced state relative to the extracellular matrix and plasma due to high concentrations of glutathione.^[89][90] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.^[91] Free LA is rapidly metabolized to a variety of shorter chain metabolites (via β-oxidation and either mono or bis-methylation) that have been identified and quantified intracellularly, in plasma and in urine.^[92][93]

The antioxidant effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C and vitamin E deficiency.^[94] LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E.^[91] LA is able to scavenge reactive oxygen and reactive nitrogen species in vitro due to long incubation times, but there is little evidence this occurs in vivo or that radical scavenging contributes to the primary mechanisms of action of LA.^[2][31] 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.^[95] 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.^[96] 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. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.^[2][31][78]

Metal chelation[link]

Owing to the presence of two thiol groups, dihydrolipoic acid is a chelating agent. It chelates both intracellular and extracellular mercury in the brain and in the body. Alpha Lipoic Acid (ALA) has a half life of 3 hours. Due to this half life issue it can be dangerous to take chelators unless they are taken on a very strict schedule (every 3–4 hours even at night, a few days on, 10–14 days off) or they can cause more mercury to enter the brain, especially within 3 months of mercury filling removal. Lipoic acid administration can significantly enhance biliary excretion of inorganic mercury in rat experiments, although it is not known if this is due to chelation by lipoic acid or some other mechanism.^[97] Lipoic acid has the potential to cross the blood–brain barrier in humans, unlike DMSA and DMPS; its effectiveness, however, is heavily dependent on the dosage and frequency of application.^[98]

(R)-Liponic acid (RLA, top) and (S)-liponic acid (SLA, down). A 1:1 mixture (racemate) of (R)- and (S)-liponic acid is called (RS)-liponic acid or (±)-liponic acid (R/S-LA).

[edit] Medicinal differences between (R)-lipoic acid (RLA) and (S)-lipoic acid (SLA)

RLA is essential for life and aerobic metabolism, and RLA is the form biosynthesized in humans and other organisms studied so far. 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 were not bioequivalent.^[65] The first synthetic procedures appeared for RLA and SLA in the mid 1950s.^{[99][100][101][102]} 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. Currently 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.^[103][104] 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).^[96][105]

SLA is generally considered safe and nontoxic. It has been shown to be more toxic to thiamine deficient rats, but the mechanism or implications of this are not clear.^[70] SLA did not exist prior to chemical synthesis in 1952.^[106][107] The S-enantiomer (SLA) can assist in the reduction of the RLA when a racemic (50% R-enantiomer and 50% S-enantiomer) mixture is given.^[108] Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.^{[109][110][111][112][113]}

Lipoic acid in vivo seems primarily to induce the oxidative stress response rather than directly scavenge free radicals (see above). This effect is specific for RLA.^[2] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.^[80]

Clinical trials and approved uses[link]

RLA is being used in a federally funded clinical trial for multiple sclerosis at Oregon Health and Science University.^[114] R-lipoic acid (RLA) is currently being used in two federally funded clinical trials at Oregon State University to test its effects in preventing heart disease and atherosclerosis.^[115][116] Alpha-lipoic acid is approved in Germany as a drug for the treatment of polyneuropathies, such as diabetic and alcoholic polyneuropathies, and liver disease.

Berkson BM. “A Conservative Triple Antioxidant Approach to the Treatment of Hepatitis C. Combination of Alpha-Lipoic Acid (Thioctic Acid), Silymarin and Selenium. Three Case Histories.” Medizinische Klinik 94(3), 1999: 84-89;

Bartter FC, Berkson BM, Gallelli J and Hiranaka P. “Treatment of Four Delayed-Mushroom-Poisoning Patients with Thioctic Acid.” in Amanita Toxins and Poisonings, eds Faulstich, H., Kommerell, B., and T.Wieland, Verlag Gerhard Witzstrock, Baden-Baden, New York 1980.

Berkson, BM. “Thioctic Acid in the Treatment of Poisoning with Alpha amanitin (acute hepatic necrosis).” Aminita Toxins and Poisonings, 1980. Amanita Toxins and Poisonings, 203 (Heidelberg: International Amanita Symposium, Nov. 1-3, 1978). eds Faulstich, H., Kommerell, B., and Th. Wieland, Verlag Gerhard Witzstrock, Baden-Baden, Koln, New York 1980.

Berkson, B. 1979. Thioctic acid in treatment of hepatotoxic mushroom poisoning . New England Journal of Medicine. 300:371.

References[link]

117. Berkson BM. “A Conservative Triple Antioxidant Approach to the Treatment of Hepatitis C. Combination of Alpha-Lipoic Acid (Thioctic Acid), Silymarin and Selenium. Three Case Histories.” Medizinische Klinik 94(3), 1999: 84-89;

118. Bartter FC, Berkson BM, Gallelli J and Hiranaka P. “Treatment of Four Delayed-Mushroom-Poisoning Patients with Thioctic Acid.” in Amanita Toxins and Poisonings, eds Faulstich, H., Kommerell, B., and T.Wieland, Verlag Gerhard Witzstrock, Baden-Baden, New York 1980.

119. Berkson, BM. “Thioctic Acid in the Treatment of Poisoning with Alpha amanitin (acute hepatic necrosis).” Aminita Toxins and Poisonings, 1980. Amanita Toxins and Poisonings, 203 (Heidelberg: International Amanita Symposium, Nov. 1-3, 1978). eds Faulstich, H., Kommerell, B., and Th. Wieland, Verlag Gerhard Witzstrock, Baden-Baden, Koln, New York 1980.

120. Berkson, B. 1979. Thioctic acid in treatment of hepatotoxic mushroom poisoning . New England Journal of Medicine. 300:371.

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Other reviews[link]

Wikimedia Commons has media related to: lipoic acid

• Jane Higdon, "Lipoic Acid", Micronutrient Information Center, Linus Pauling Institute, Oregon State University