Lipoic acid

Source: Wikipedia, the free encyclopedia.
Not to be confused with
alpha-Linolenic acid
.
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
3D model (
JSmol
)
81851
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.012.793 Edit this at Wikidata
EC Number
  • 214-071-2
IUPHAR/BPS
KEGG
MeSH Lipoic+acid
UNII
  • 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 checkY
    Key: AGBQKNBQESQNJD-SSDOTTSWSA-N checkY
  • 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
  • O=C(O)CCCC[C@H]1SSCC1
Properties
C8H14O2S2
Molar mass 206.32 g·mol−1
Appearance Yellow needle-like crystals
Melting point 60–62 °C (140–144 °F; 333–335 K)
Very Slightly Soluble(0.24 g/L)[1]
Solubility in ethanol 50 mg/mL Soluble
Pharmacology
A16AX01 (WHO)
Pharmacokinetics:
30% (oral)[2]
Related compounds
Related compounds
 Lipoamide
Asparagusic acid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an

conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions.[3]
Only the (R)-(+)-
aerobic metabolism because RLA is an essential cofactor of many enzyme complexes.[3]

Physical and chemical properties

Lipoic acid (LA), also known as α-lipoic acid,

disulfide bond and is thus considered to be oxidized although either sulfur atom can exist in higher oxidation states.[3]

The carbon atom at C6 is

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.[6][7]

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 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.[8]

HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are targets of the reduced form (open disulfide) of (R)-lipoic acid. [9]

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,

lipoate protein ligase that attaches it covalently to the correct protein. The ligase activity of this enzyme requires ATP.[11]

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[12] or pantothenic acid[13] reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.

Enzymatic activity

Lipoic acid is a

glycine cleavage complex or glycine dehydrogenase.[3]

Lipoic acid is the cofactor of the following enzymes in humans:[14][15][16]

EC-number Enzyme Gene Multienzyme complex Type of metabolism
EC 2.3.1.12 dihydrolipoyl transacetylase (E2)
DLAT
 pyruvate dehydrogenase complex (PDC)
energy metabolism
EC 2.3.1.61 dihydrolipoyl succinyltransferase (E2) DLST oxoglutarate dehydrogenase complex (OGDC)
2-oxoadipate dehydrogenase complex (OADHC)
amino acid metabolism
EC 2.3.1.168 dihydrolipoyl transacylase (E2) DBT branched-chain α-ketoacid dehydrogenase complex (BCKDC)
H-protein GCSH glycine cleavage system (GCS)

The most-studied of these is the pyruvate dehydrogenase complex.[3] 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.[3] 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.[17]

Lipoic acid serves as co-factor to the

acetyl coenzyme A.[3]

The

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.[18]

Biological sources and degradation

Lipoic acid is present in many foods in which it is bound to lysine in proteins,[3] but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[19] Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources.[3] 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.[20] 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.

alcalase, respectively.[22][23][24]

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.[25] 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.[3] Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for cysteine.[3]

Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.[3][26] 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.[26] Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.[3][27] 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 (CMAMMA) due to ACSF3 deficiency, mitochondrial fatty acid synthesis (mtFASII), which is the precursor reaction of lipoic acid biosynthesis, is impaired.[28][29] The result is a reduced lipoylation degree of important mitochondrial enzymes, such as pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase complex (α-KGDHC).[29] Supplementation with lipoic acid does not restore mitochondrial function.[30][29]

Chemical synthesis

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.

eutomer (the nutritionally and therapeutically preferred form).[40][41]

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.[42] Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.[42]

The various forms of LA are not bioequivalent.[33][non-primary source needed] Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.[42]

The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.[43]

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.[4] Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.[44] 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.[4][45] 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.[46] 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.[40] 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.[4][45][47]

All the

thiol-disulfide exchange reactions.[55]

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.[47][56] This stress response indirectly improves the antioxidant capacity of the cell.[4]

The (S)-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.[57][58]

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by competitive inhibition.[59][60][61][62][63]

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.[3]

Although the body can synthesize LA, it can also be absorbed from the diet. Dietary supplementation in doses from 200–600 mg is likely to provide up to 1000 times the amount available from a regular diet. Gastrointestinal absorption is variable and decreases with the use of food. It is therefore recommended that dietary LA be taken 30–60 minutes before or at least 120 minutes after a meal. Maximum blood levels of LA are achieved 30–60 minutes after dietary supplementation, and it is thought to be largely metabolized in the liver.[64]

In Germany, LA is approved as a drug for the treatment of diabetic neuropathy since 1966 and is available as a non-prescription pharmaceutical.[65]

Clinical research

According to the

mitochondrial disorders.[68] A 2018 review recommended ALA as an anti-obesity supplement with low dosage (< 600 mg/day) for a short period (<10 weeks); however, it is too expensive to be practical as a complementary therapy for obesity.[69]

Other lipoic acids

See also

References

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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Lipoic_acid&oldid=1212457618"