Lipoic acid

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Lipoic acid (LA) 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.[2] 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 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 in aerobic metabolism, specifically the pyruvate dehydrogenase complex (PDC or PDHC). 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.

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.[3][4][5][6][7][8][9] Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, thiol-disulfide exchange reactions.[10]

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