Lipoic acid
Encyclopedia
Lipoic acid also known as α-lipoic acid and Alpha Lipoic Acid (ALA) is an organosulfur compound derived from octanoic acid
. LA contains two vicinal
sulfur atoms (at C6 and C8) attached via 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. 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 a number of 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 physiological conditions. Although the intracellular environment is strongly reducing, both free LA and its reduced form, dihydrolipoic acid
(DHLA) have been detected within cells after administration of LA. Most endogenously produced RLA is not “free”, because octanoic acid, the precursor to RLA, is attached to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached via 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), although it is a cofactor in other enzymatic systems as well (described below).
mechanism, by lipoyl synthase
. The sulfurs are from the lipoyl synthase
polypeptide. 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 the action of a specific enzyme, called lipoamidase. 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.
(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. 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. 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. The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.
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.
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. 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.
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. 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. 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. Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiological 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. Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles. It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2).
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. 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. 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”. 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.
Several papers found RLA and acetyl carnitine reversed age-related markers in old rats to youthful levels.
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. This stress response indirectly improves the antioxidant capacity of the cell.
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. Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.
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.
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. Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms. 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.
The antioxidant
effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C
and vitamin E
deficiency. LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E. 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. 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. 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. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.
is a chelating agent
. 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. 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.
RLA is essential for life and aerobic metabolism, and RLA is the form biosynthesised 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. 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. Currently most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in 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).
SLA is generally considered safe and non-toxic. It has been shown to be more toxic to thiamine deficient rats, but the mechanism or implications of this are not clear. SLA did not exist prior to chemical synthesis in 1952. 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. Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition
.
More recently the primary effect of lipoic acid is not as an in vivo free radical scavenger, but rather an inducer of the oxidative stress response (see above). This effect is specific for RLA. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.
Caprylic acid
Caprylic acid is the common name for the eight-carbon saturated fatty acid known by the systematic name octanoic acid. It is found naturally in the milk of various mammals, and it is a minor constituent of coconut oil and palm kernel oil...
. LA contains two vicinal
Vicinal (chemistry)
In chemistry vicinal stands for any two functional groups bonded to two adjacent carbon atoms. For example the molecule 2,3-dibromobutane carries two vicinal bromine atoms and 1,3-dibromobutane does not....
sulfur atoms (at C6 and C8) attached via a disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
and is thus considered to be oxidized (although either sulfur atom can exist in higher oxidation states). The carbon atom at C6 is chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
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. 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 a number of 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 physiological conditions. Although the intracellular environment is strongly reducing, both free LA and its reduced form, dihydrolipoic acid
Dihydrolipoic acid
Dihydrolipoic acid is an organic compound that is the reduced form of lipoic acid. This carboxylic acid features a pair of thiol groups. It is optically active but only the R-enantiomer is biochemically significant. The lipoic acid/dihydrolipoic acid pair participate in a variety of biochemical...
(DHLA) have been detected within cells after administration of LA. Most endogenously produced RLA is not “free”, because octanoic acid, the precursor to RLA, is attached to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached via 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), although it is a cofactor in other enzymatic systems as well (described below).
Biosynthesis and attachment
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 the mitochondria is used for this purpose. 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 methionineS-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
mechanism, by lipoyl synthase
Lipoyl synthase
In enzymology, a lipoyl synthase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are protein N6-lysine, sulfur, and S-adenosyl-L-methionine, whereas its 3 products are protein N6-lysine, L-methionine, and 5'-deoxyadenosine.This enzyme belongs to the family of...
. The sulfurs are from the lipoyl synthase
Lipoyl synthase
In enzymology, a lipoyl synthase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are protein N6-lysine, sulfur, and S-adenosyl-L-methionine, whereas its 3 products are protein N6-lysine, L-methionine, and 5'-deoxyadenosine.This enzyme belongs to the family of...
polypeptide. 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 the action of a specific enzyme, called lipoamidase. Free lipoate can be attached to the lipoyl domain by the enzyme lipoate protein ligase. The ligase
Ligase
In biochemistry, ligase is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group dependent to one of the larger molecules...
activity of this enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
requires ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. Lipoate protein ligases proceed via an enzyme bound lipoyl adenylate intermediate.
Lipoic acid-dependent complexes
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 dehydrogenaseAcetoin dehydrogenase
Acetoin dehydrogenase or diacetyl reductase is an enzyme that catalyzes the transformation of acetoin to diacetyl....
(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
Dihydrolipoamide dehydrogenase
Dihydrolipoamide dehydrogenase , also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that degrades lipoamide, and produces dihydrolipoamide....
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 geometry of the PDH E2 core is cubic
Cube
In geometry, a cube is a three-dimensional solid object bounded by six square faces, facets or sides, with three meeting at each vertex. The cube can also be called a regular hexahedron and is one of the five Platonic solids. It is a special kind of square prism, of rectangular parallelepiped and...
in Gram-negative bacteria or dodecahedral in Eukaryotes and Gram-positive bacteria. Interestingly the 2-OGDH and BCDH geometry is always cubic. 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. The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.
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
Acetoin dehydrogenase
Acetoin dehydrogenase or diacetyl reductase is an enzyme that catalyzes the transformation of acetoin to diacetyl....
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
Glycine cleavage system
The glycine cleavage system is also known as the glycine decarboxylase complex or GCS. The system is a series of enzymes that are triggered in response to high concentrations of the amino acid glycine. The glycine cleavage system is composed of four proteins: the T-protein, P-protein, L-protein,...
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.
Biological sources and degradation
Lipoic acid is found in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract. Naturally occurring lipoic acid is always covalently bound and not immediately available from dietary sources. Additionally, the amount of lipoic acid present is very low. For example: 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. 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.
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. 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. 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. Lipoate is the conjugate base of lipoic acid and as such is the most prevalent form under physiological 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. Endogenous RLA has been found outside the mitochondria associated with the nucleus, peroxisomes and other organelles. It has been suggested that the reduced form, R-DHLA may be the substrate for membrane-associated prostaglandin E-2 synthase (mPGES2).
Pharmacology and medical uses of free lipoic acid
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. 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. Humans biosynthesize lipoic acid and it is not a required vitamin, so no Recommended Daily Allowance (RDA) has been established.Possible beneficial effects
Lipoic acid has been the subject of numerous research studies and clinical trials:- Prevent organ dysfunction
- Reduce endothelial dysfunction and improve albuminuria
- Treat or prevent cardiovascular disease
- Accelerate chronic wound healing
- Reduce levels of ADMAAsymmetric dimethylarginineAsymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...
in diabetic end-stage renal disease patients on hemodialysis
- Management of burning mouth syndrome
- Reduce iron overload
- Treat metabolic syndrome
- Improve or prevent age-related cognitive dysfunction
- Prevent or slow the progression of Alzheimer’s Disease
- Prevent erectile dysfunction (animal models but anecdotally applies to humans as well)
- Prevent migraines
- Treat multiple sclerosis
- Treat chronic diseases associated with oxidative stress
- Reduce inflammation
- Inhibit advanced glycation end products (AGE) treat peripheral artery disease.
RLA is a classic example of an orthomolecular nutrient, in the original sense of Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
. 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. 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. 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
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
status, but is today considered to be a “conditionally essential nutrient”. 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.
Several papers found RLA and acetyl carnitine reversed age-related markers in old rats to youthful levels.
RLA may function in vivo like a B-vitamin and at higher doses like plant-derived nutrients, such as curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
, sulphoraphane, resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, 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.
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. Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.
Antioxidant and prooxidant effects of lipoic acid
All of the disulfideDisulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
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
Glutathione reductase
Glutathione reductase, also known as GSR or GR, is an enzyme that reduces glutathione disulfide to the sulfhydryl form GSH, which is an important cellular antioxidant....
(GR) and thioredoxin reductase
Thioredoxin reductase
Thioredoxin Reductases are the only known enzymes to reduce thioredoxin . Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. Both classes are flavoproteins which function as homodimers...
(Trx1) and two mitochondrial enzymes lipoamide dehydrogenase and thioredoxin reductase
Thioredoxin reductase
Thioredoxin Reductases are the only known enzymes to reduce thioredoxin . Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. Both classes are flavoproteins which function as homodimers...
(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.
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. Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms. 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.
The antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
effects of LA were demonstrated when it was found to prevent the symptoms of vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
and vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
deficiency. LA is reduced intracellularly to dihydrolipoic acid, which in cell culture regenerates by reduction of antioxidant radicals, such as vitamin C and vitamin E. 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. 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. 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. Paradoxically, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.
Metal chelation
Owing to the presence of two thiol groups, dihydrolipoic acidDihydrolipoic acid
Dihydrolipoic acid is an organic compound that is the reduced form of lipoic acid. This carboxylic acid features a pair of thiol groups. It is optically active but only the R-enantiomer is biochemically significant. The lipoic acid/dihydrolipoic acid pair participate in a variety of biochemical...
is a chelating agent
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
. 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. Lipoic acid has the potential to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
in humans, unlike DMSA and DMPS
2,3-Dimercapto-1-propanesulfonic acid
2,3-Dimercapto-1-propanesulfonic acid and its sodium salt are chelating agents that form complexes with various heavy metals. They are related to dimercaprol, which is another chelating agent....
; its effectiveness, however, is heavily dependent on the dosage and frequency of application.
Medicinal differences between R-lipoic acid and S-lipoic acid
R lipoic acid is marketed as dietary supplement or topical treatment by different companies. They claim that R lipoic acid is superior to the cheaper racemic mixture. While R lipoic acid appears to be the form responsible for the beneficial effect (NRF2 activation), convincing evidence for a harmful effect of S lipoic acid is lacking. This is complicated by the lack of knowledge regarding the exact mechanism(s) of how R and S lipoic acid affect organisms when taken as a supplement. As such, the topic can be biased and should be considered carefully below.RLA is essential for life and aerobic metabolism, and RLA is the form biosynthesised 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. 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. Currently most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in 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
Eutomer
The eutomer is the molecular chiral enantiomer having the desired bioactivity, e. g. as as an active ingredient in a drug. On the other hand the enantiomer of the eutomer having the undesired bioactivity is called distomer....
(the nutritionally and therapeutically preferred form).
SLA is generally considered safe and non-toxic. It has been shown to be more toxic to thiamine deficient rats, but the mechanism or implications of this are not clear. SLA did not exist prior to chemical synthesis in 1952. 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. Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition
Competitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
.
More recently the primary effect of lipoic acid is not as an in vivo free radical scavenger, but rather an inducer of the oxidative stress response (see above). This effect is specific for RLA. Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.