Lipoic Acid

Lipoic acid is a naturally occurring organosulphur compound derived from octanoic acid and plays a fundamental role in aerobic metabolism. It functions both as a covalently bound cofactor in several mitochondrial enzyme complexes and as a redox-active molecule involved in maintaining metabolic balance. Although organisms synthesise the compound endogenously, it is also consumed as a dietary supplement or as a pharmaceutical preparation in certain countries. Under physiological conditions, lipoic acid predominantly exists as its conjugate base, lipoate.

Physical and Chemical Characteristics

Lipoic acid contains two sulphur atoms connected by a disulphide bond within a 1,2-dithiolane ring, in addition to possessing a terminal carboxylic acid group. This five-membered ring structure gives the molecule notable redox activity. In its oxidised form, the sulphur atoms are linked by a disulphide bond, whereas in the reduced form, known as dihydrolipoic acid, each sulphur atom exists as a thiol.
The naturally occurring form is the R-enantiomer (R-lipoic acid, RLA), which is produced by living organisms and is essential for numerous enzyme-mediated biochemical reactions. By contrast, S-lipoic acid (SLA) does not occur in nature and is produced synthetically. Commercial preparations of lipoic acid may be racemic (RS-lipoic acid), although modern manufacturing techniques increasingly enable the production of the isolated R-enantiomer with high optical purity. In its purified form, lipoic acid is a yellow crystalline solid.

Biological Function and Enzymatic Roles

Lipoic acid acts as a covalently bound cofactor for at least five major enzyme systems, many of which are central to mitochondrial energy metabolism. Significant examples include:

• Pyruvate dehydrogenase complex (PDC)Converts pyruvate to acetyl-CoA, linking glycolysis to the citric acid cycle.
• α-Ketoglutarate dehydrogenase complex (KGDHC)Catalyses a key oxidative decarboxylation step within the citric acid cycle.
• Branched-chain α-keto acid dehydrogenase complexInvolved in the catabolism of valine, leucine, and isoleucine.
• Oxoadipate dehydrogenase complexFunctions in lysine and tryptophan metabolism.
• Glycine cleavage system (GCS)Regulates glycine concentrations and supports one-carbon metabolism.

The reduced form of R-lipoic acid has also been shown to interact with specific histone deacetylases (HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10), indicating its involvement in broader regulatory processes.
Within these enzyme complexes, lipoic acid is covalently attached to a lysine residue via an amide bond, forming a lipoyl moiety. This structure functions as a mobile carrier that transfers reaction intermediates between active sites. For example, in the PDC and related multi-enzyme complexes, the lipoyl domain shuttles acyl groups and participates in redox cycling, enabling efficient metabolic throughput.

Biosynthesis and Protein Attachment

Endogenous biosynthesis of lipoic acid takes place in the mitochondria. The precursor, octanoic acid, originates from mitochondrial fatty acid synthesis in the form of octanoyl-acyl carrier protein (octanoyl-ACP). The biosynthetic process involves several coordinated steps:

• Transfer of the octanoyl group from ACP to the target lysine residue of a lipoyl domain protein, catalysed by lipoyl-octanoyl transferase.
• Insertion of two sulphur atoms into the octanoyl chain via a radical S-adenosylmethionine (SAM) mechanism mediated by lipoyl synthase.

As a result, lipoic acid is synthesised in its protein-bound form, and free lipoic acid is generally not produced within cells. Lipoic acid can be released only upon protein turnover or through the activity of lipoamidase.
Some organisms can also attach free dietary lipoate to appropriate enzyme complexes through the action of lipoate protein ligase, an ATP-dependent process that recognises the correct substrate protein.

Cellular Transport and Competition

Uptake of lipoic acid into cells occurs via the sodium-dependent multivitamin transporter (SMVT). This system also transports pantothenic acid (vitamin B₅) and biotin (vitamin B₇), creating competitive interactions. Elevated intake of lipoic acid has been shown to reduce biotin absorption and potentially influence the activity of biotin-dependent enzymes, illustrating the transporter’s shared substrate properties.

Enzymatic Activity and Structural Organisation

Lipoylated enzyme complexes typically comprise multiple subunits arranged around a central core. For example, in the pyruvate dehydrogenase complex:

• E1 (pyruvate dehydrogenase) performs decarboxylation.
• E2 (dihydrolipoyl transacetylase) contains one or more lipoyl domains and mediates acyl transfer.
• E3 (dihydrolipoamide dehydrogenase) regenerates the oxidised form of lipoamide.

The lipoyl domain is positioned on a flexible linker arm, allowing it to ferry acyl or methylamine intermediates between the catalytic sites. The number of lipoyl domains varies widely among organisms, typically from one to three, although experimental modifications suggest that enzyme function becomes impaired only when more than three such domains are added.
Lipoic acid is also a cofactor in the acetoin dehydrogenase complex, which converts acetoin to acetaldehyde and acetyl-CoA. In the glycine cleavage system, the H protein serves as a mobile lipoylated carrier, supporting the transfer of methylamine to tetrahydrofolate to form methylene-THF, a key intermediate in amino-acid biosynthesis.

Biological Sources and Dietary Availability

Lipoic acid is present in many foods but is typically found in the form of lipoyl-lysine, tightly bound to proteins. Dietary sources that contain higher levels include:

• Liver, kidney, and heart
• Spinach and other leafy greens
• Broccoli
• Yeast extract

Despite its presence in various foods, the total amount available from dietary sources is small, and natural protein-bound lipoic acid is not readily accessible for absorption. Studies historically required extremely large quantities of biological material to purify even minute amounts of lipoic acid, demonstrating its low natural abundance.
Synthetic forms, therefore, dominate the commercial supply used for supplementation. Enzymatic or acid hydrolysis can liberate protein-bound lipoic acid for analytical measurements, but baseline levels of free lipoic acid are generally undetectable in human plasma.

Degradation and Metabolic Fate

In mammals, supplemented lipoic acid undergoes several metabolic transformations, including:

• Formation of tetranorlipoic acid, a shortened-chain metabolite
• Sulphur oxidation, producing various sulfoxide derivatives
• S-methylation of sulphide groups
• Conjugation with glycine

These pathways resemble those observed in other species such as mice. Current evidence suggests that mammals cannot utilise lipoic acid as a significant sulphur source.
Both synthetic lipoamide and lipoyl-lysine derivatives are rapidly cleaved by serum lipoamidases to release free R-lipoic acid. However, digestive enzymes are unable to hydrolyse the amide bond in lipoic acid–lysine conjugates derived from food proteins, limiting the availability of free lipoate from dietary intake.

Disorders Involving Lipoic Acid Metabolism

Defects in mitochondrial fatty acid synthesis can impair lipoic acid biosynthesis. Notably, combined malonic and methylmalonic aciduria (CMAMMA) caused by ACSF3 deficiency disrupts the production of octanoate, the essential precursor for lipoylation. This leads to reduced modification of mitochondrial enzymes such as PDC and KGDHC. Supplementation with lipoic acid does not correct the underlying deficits in mitochondrial function, as the biosynthetic attachment machinery remains compromised.

Chemical Synthesis and Industrial Production

S-lipoic acid was first synthesised in 1952, marking the beginning of large-scale chemical production. Racemic RS-lipoic acid became widely used in clinical contexts during the mid-20th century, even though the biological properties of the two enantiomers differ.
Subsequent advances in stereoselective synthesis and chiral resolution enabled efficient production of high-purity R-lipoic acid. Contemporary industrial processes—mainly conducted in China, with smaller contributions from Italy, Germany, and Japan—provide RLA, SLA, and RSLA for global use. The foundational production method for RLA was derived from research by Georg Lang and later patented.
Although both stereoisomers may participate in biological reactions, the R-form is generally considered the eutomer, showing higher nutritional and therapeutic relevance. Consequently, there has been increasing interest in producing and using enantiomerically pure R-lipoic acid rather than racemic preparations.

Metabolic Significance

Lipoic acid is indispensable for oxidative decarboxylation reactions and for linking carbohydrate, amino-acid, and fatty-acid metabolism. Its unique redox characteristics, flexible attachment to lipoyl domains, and essential role in multi-enzyme systems underline its biochemical importance. Research continues to explore its broader physiological and regulatory functions, particularly within mitochondrial biology and metabolic disease.