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, 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.

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-oxo(keto)adipate 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 (open dithiol) of (R)-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. 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.

{| class="wikitable"

!EC-number

!Enzyme

!Gene

!Multienzyme complex

!Role of the complex

|EC 2.3.1.12

|dihydrolipoyl transacetylase (E2)

|DLAT

|pyruvate dehydrogenase complex (PDC)

|Connection of glycolysis with the citric acid cycle

| rowspan="2" |EC 2.3.1.61

| rowspan="2" |dihydrolipoyl succinyltransferase (E2)

| rowspan="2" |DLST

|oxoglutarate dehydrogenase complex (OGDC)

|Citric acid cycle enzyme

|2-oxoadipate dehydrogenase complex (OADHC)

|Lysine, tryptophan and hydroxylysine degradation

|EC 2.3.1.168

|dihydrolipoyl transacylase (E2)

|DBT

|branched-chain α-ketoacid dehydrogenase complex (BCKDC)

|Leucine, isoleucine and valine degradation

|H-protein

|GCSH

|glycine cleavage system (GCS)

|Glycine and serine metabolism, folate metabolism

The most-studied of these is the pyruvate dehydrogenase 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.

Biological sources and degradation

Lipoic acid is present in many foods in which it is bound to lysine in proteins, Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources. 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. Degradation to tetranorlipoic acid in which the four CH2-groups between the ring and the carboxilic acid are removed, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide occur.

Diseases

Combined malonic and methylmalonic aciduria (CMAMMA)

In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, mitochondrial fatty acid synthesis (mtFAS), 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 (PDC) and α-ketoglutarate dehydrogenase complex (α-KGDHC). 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. 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. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.

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. 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. Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.

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

The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.

Uses

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 marketed as antioxidants and pertaining to cellular glucose utilization for metabolic disorders and type 2 diabetes.

In Germany, LA is approved as a drug for the treatment of diabetic neuropathy since 1966 and is available as a non-prescription pharmaceutical.

Clinical research

Although lipoic acid has been tested in clinical research for potential use as a therapy for various diseases, the studies have been of limited quality, with no conclusive evidence that it is warranted as a therapeutic, as of 2026.

As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for diabetic neuropathy, but has been proven reasonably safe and effective. As of 2012, there was no good evidence alpha lipoic acid helps people with mitochondrial disorders.

A 2018 review found that ALA had a small effect to reduce body weight, but is not cost-effective as a dietary supplement.

A 2025 study indicated a positive effect in a cellular model of Friedreich's ataxia.

Other lipoic acids

β-lipoic acid is a thiosulfinate of α-lipoic acid