Lipoic acid

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Lipoic acid
IUPAC name
Other names α-lipoic acid (alpha lipoic acid), thioctic acid, 6,8-dithiooctanoic acid
Identifiers
CAS number 1200-22-2
PubChem 6112
MeSH Lipoic+acid
SMILES
Properties
Molecular formula C8H14O2S2
Molar mass 206.33 g/mol
Appearance yellow needle-like crystals
Pharmacology
Bioavailability 30% (oral)[1]
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox references

Lipoic acid is an organosulfur compound, one enantiomer of which is an essential cofactor for many enzyme complexes. This yellow solid is a carboxylic acid and features a cyclic disulfide, or ditholane ring, functional group. The R-enantiomer is biosynthesized and used as a cofactor. It is essential for aerobic life and is a common and sometimes controversial dietary supplement. It is usually called "lipoic acid," but this is not the form it takes in life. dihydrolipoic acid is the reduced form which is mostly how the sulfurs exist intracellularly. "Lipoate" is the conjugate base of lipoic acid, and this is the form carboxylic acids take at physiological conditions. So free lipoic acid inside the cell could correctly be called dihydrolipoate. Most intracellular lipoic acid is not free, because it is made and attached to the enzyme complexes that use it. As a cofactor it is covalently bound via and amide bond to a specific lysine residue of lipoyl domains. One of the most visible roles of lipoic acid is as a cofactor in aerobic metabolism, specifically the pyruvate dehydrogenase complex. Lipoate participates in transfer of acyl or methylamine groups in 2-oxoacid dehydrogenases (2-OADH) and glycine cleavage complexes (GCV), respectively.[2]

Contents

[edit] History

Lipoate was first called pyruvate oxidation factor (POF) by Irwin C. Gunsalus, the former chair of Biochemistry at the University of Illinois at Urbana-Champaign.[3][4] This was after the observation by many groups that POF functioned as an essential growth factor for Enterococci, which lack the ability to make lipoate.[5] The structure was determined in a collaboration of Gunsalus with Lester Reed and Eli Lilly; the synthetic compound designated α-lipoic acid proved to be the correct molecule.[6] The configuration found in vivo was later found to be the R-enantiomer.[7]

The first human clinical studies using alpha-lipoic acid (ALA) in the United States were conducted by Fredrick C. Bartter, Burton M. Berkson, and associates from the National Institutes of Health in the 1970’s.[8][9][10] They administered intravenous ALA to 79 people with acute and severe liver damage at various medical centers across the United States and 75 recovered full liver function. Drs. Bartter and Berkson were appointed by the FDA as principal investigators for this therapeutic agent as an investigational drug and Dr. Berkson went on to use it successfully for the treatment of chronic liver disease (viral hepatitis, autoimmune hepatitis, etc).[11]

[edit] Biosynthesis and attachment

The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis. In eukaryotes a second fatty acid biosynthetic pathway in the mitochondria is used for this purpose.[12][13] The octanoate is transferred from a thioester of acyl carrier protein to a 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 methionine mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide.[14] 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[15]. Free lipoic can be attached to the lipoyl domain by the enzyme lipoate protein ligase. Like all ligases, this enzyme requires ATP. Lipoate protein ligases proceed via a enzyme bound lipoyl adenylate intermediate. [16]

[edit] 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 dehydrogenase (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.[17][18] 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.[19] 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.[20] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[21]

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.[22]

[edit] Biological sources

Lipoic acid is found in almost all foods, but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.[23][24] Naturally occuring 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 30mg of lipoic acid.[25] As a result, all lipoic acid available as a supplement is chemically synthesized.

[edit] Use as a dietary supplement

Since the early 1990s lipoic acid has been consumed as a dietary supplement, typical doses are 100–200 mg/day. A chronic/carcinogenicity study in rats reported that racemic lipoic acid was found to be non-carcinogenic and did not show any evidence of target organ toxicity. The NOAEL is considered to be 60 mg/kg bw/day.[26]

In addition, because of ALA’s ability to modify gene expression by stabilizing NF kappa B transcription factor, Burton M. Berkson started using ALA for the treatment of various cancers for which no effective treatments exist. In a 2006 publication, he and co-authors described the long term survival of a patient with metastatic pancreatic cancer using ALA, low dose naltrexone (LDN), and various oral antioxidants.[27] A 2007 publication of a case study described the complete reversal of the signs and symptoms of a B-cell lymphoma in a patient using less than one month of IV ALA and 6 months of LDN. [28]

[edit] Antioxidant

Lipoic acid was first postulated to be an effective antioxidant when it was found it prevented the symptoms of vitamin C and vitamin E deficiency. It is able to scavenge reactive species in vitro, though there is little or no evidence that this actually occurs in vivo. The relatively good scavenging activity of lipoic acid is due to the strained conformation of the 5-membered ring in the intramolecular disulfide.[29] In cells, lipoic acid can theoretically be reduced to dihydrolipoic acid (ΔE= -0.288), though significant quantities of dihydrolipoic acid derived from orally-ingested lipoic acid have never been demonstrated. Dihydrolipoic acid is able to regenerate (reduce) antioxidants, such as glutathione, vitamin C and vitamin E. [30][31][32] Recent findings suggest that lipoic acid curative effects is due to modulation of regulation in eukaryotes. This occurs due to lipoic acid acting as an oxidant, not a reductant. [33]

[edit] Disease Treatment

Lipoic acid has been shown in cell culture experiments to increase cellular uptake of glucose by recruiting the glucose transporter GLUT4 to the cell membrane, suggesting its use in diabetes.[34][35] Studies of rat aging have suggested that the use of L-carnitine and lipoic acid results in improved memory performance and delayed structural mitochondrial decay.[36] As a result, it may be helpful for people with Alzheimer's disease or Parkinson's disease.[37] In 2009 a study found that it reduced triglycerides in mice.[38]

[edit] Use as a chelator

Owing to the presence of two thiol groups, dihydrolipoic acid is a chelating agent, but there is no evidence that this reactivity is biologically relevant.[39] As a result, lipoic acid is not approved by the U.S. Food and Drug Administration as a chelating agent.

[edit] The S-enantiomer

Sister project Wikimedia Commons has media related to: lipoic acid

Normally, only the R-enantiomer of lipoic acid occurs naturally, but the S-enantiomer can assist in the reduction of the R-enantiomer when a racemic mixture is given.[40] However, some recent studies have suggested that the S-enantiomer in fact has an inhibiting effect on the R-enantiomer, reducing its biological activity substantially and actually adding to oxidative stress rather than reducing it. Furthermore, the S-enantiomer has been found to reduce the expression of GLUT4, responsible for glucose uptake in cells, and hence to reduce insulin sensitivity.[41]

[edit] References

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  15. ^ Jiang Y, Cronan JE. (2005). "Expression cloning and demonstration of Enterococcus faecalis lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase.". J Biol Chem. 280 (3): 2244-56. PMID 15528186. 
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  21. ^ Omelchenko MV, Makarova KS, and Koonin EV (2002). "Recurrent intragenomic recombination leading to sequence homogenization during the evolution of the lipoyl-binding domain". J FEMS Microbiol. Lett 209: 255–260. doi:10.1111/j.1574-6968.2002.tb11140.x. 
  22. ^ Douce R, Bourguignon J, Neuburger M, and Rebeille F (2001). "The glycine decarboxylase system: a fascinating complex". . Trends Plant Sci 6: 167–176. doi:10.1016/S1360-1385(01)01892-1. 
  23. ^ Higdon, Jane. "Linus Pauling Institute at Oregon State University: Micronutrient Information Center: Lipoic Acid". http://lpi.oregonstate.edu/infocenter/othernuts/la/index.html#food_source. 
  24. ^ "Treating Type 2 Diabetes with Dietary Supplements". http://nccam.nih.gov/health/diabetes/#alpha. 
  25. ^ Reed LJ (Oct 2001). "A Trail of Research from Lipoic Acid to alpha-Keto Acid Dehydrogenase Complexes". J Biol Chem. 276 (42): 38329-36. PMID 11477096. 
  26. ^ Cremer DR Rabeler R Roberts A Lynch B (2006). "-term safety of alpha-lipoic acid (ALA) consumption: A 2-year study". Long Regul Toxicol Pharmacol 46: 193–201. doi:10.1016/j.yrtph.2006.06.003. 
  27. ^ Berkson, BM, Rubin D, and Berkson AJ “Long term survival of a 46 year old man with pancreatic cancer and liver metastases and treated with intravenous alpha lipoic acid and low dose naltrexone” Integrative Cancer Therapies 5;1 March 2006,83-89
  28. ^ Burton M. Berkson, Daniel M. Rubin and Arthur J. Berkson [Reversal of Signs and Symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone http://www.ldn4cancer.com/files/berkson-b-cell-lymphoma-paper.pdf] Integrative Cancer Therapies 6(3); September 2007, 293-296 DOI: 10.1177/1534735407306358
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  30. ^ Biewenga GP Haenen GRMM Bast A (1997). "The pharmacology of the antioxidant lipoic acid". Gen Pharmacol 29: 315–331. 
  31. ^ Packer L, Witt EH, and Tritschler HJ (1995). "alpha-Lipoic acid as a biological antioxidant". Free Radic Biol Med 19: 227–250. doi:10.1016/0891-5849(95)00017-R. 
  32. ^ Biewenga GP Haenen GRMM Bast A (1997). "The pharmacology of the antioxidant lipoic acid". Gen Pharmacol 29: 315–331. 
  33. ^ McCarty MF, Barroso-Aranda J, Contreras F. (Jan pages=29-33 2009). "The “rejuvenatory” impact of lipoic acid on mitochondrial function in aging rats may reflect induction and activation of PPAR-γ coactivator-1α". Medical Hypotheses 72 (1). PMID 18789599. 
  34. ^ Henriksen EJ (2006). "Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes". Free Radic Biol Med 40 (1): 3–12. doi:10.1016/j.freeradbiomed.2005.04.002. 
  35. ^ Packer L, Kraemer K, Rimbach G (2001). "Molecular aspects of lipoic acid in the prevention of diabetes complications". Nutrition 17 (10): 888–95. doi:10.1016/S0899-9007(01)00658-X. 
  36. ^ B. N. Ames, J. Liu (2004). "Delaying the Mitochondrial Decay of Aging with Acetylcarnitine". Ann. N.Y. Acad. Sci. 1033: 108–116. doi:10.1196/annals.1320.010. PMID 15591008. 
  37. ^ G. Aliev, J. Liu, J. C. Shenk, K. Fischbach, G. J. Pacheco, S. G. Chen, M. E. Obrenovich, W. F. Ward, A. G. Richardson, M. A. Smith, E. Gasimov, G. Perry, B. N. Ames (2008). "Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats". J. Cell. Mol. Med. Epub ahead of print: 080329002216155. doi:10.1111/j.1582-4934.2008.00324.x. 
  38. ^ Butler JA et al. (2009). Archives of Biochemistry and Biophysics. doi:10.1016/j.abb.2009.01.024.  Press release.
  39. ^ Aposhian HV, Morgan DL, Queen HL, Maiorino RM, Aposhian MM. (May 2003). "Vitamin C, glutathione, or lipoic acid did not decrease brain or kidney mercury in rats exposed to mercury vapor.". J Toxicol Clin Toxicol. 41 (4): 339-47. PMID 12870874. 
  40. ^ Biewenga GP Haenen GRMM Groen BH Biewenga JE Van Grondelle R and Bast A (1997). "Combined non-enzymatic and enzymatic reduction favors bioactivation of racemic lipoic acid: an advantage of a racemic drug?". Chirality 9: 362–366. doi:10.1002/(SICI)1520-636X(1997)9:4<362::AID-CHIR8>3.0.CO;2-F. 
  41. ^ Loffelhardt S, Bonaventura C, Locher M, Borbe HO, Bisswanger H (1995). "Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex". Biochem Pharmacol 50 (5): 637–46. doi:10.1016/0006-2952(95)00175-Y. 

[edit] Other reviews

v • d • e
Enzyme cofactors
Coenzymes
vitamins: NAD+ (B3) · NADP+ (B3) · Coenzyme A (B5) · THF / H4F (B9), DHF, MTHF · Ascorbic acid (C) · Menaquinone (K) · Coenzyme F420
non-vitamins: ATP · CTP · SAM · PAPS · GSH · Coenzyme B · Coenzyme M · Coenzyme Q · Methanofuran · BH4 · H4MPT
Organic prosthetic groups
vitamins: TPP / ThDP (B1) · FMN, FAD (B2) · PLP / P5P (B6) · Biotin (B7) · Methylcobalamin, Cobamamide (B12)
non-vitamins: Haem / Heme (A, B, C, O) · Lipoic acid · Molybdopterin · PQQ
Metal prosthetic groups
Ca2+ · Cu2+ · Fe2+, Fe3+ · Mg2+ · Mn2+ · Mo · Ni2+ · Se · Zn2+
Major families of biochemicals
Saccharides/Carbohydrates/Glycosides · Amino acids/Peptides/Proteins/Glycoproteins · Lipids/Terpenes/Steroids/Carotenoids · Alkaloids/Nucleobases/Nucleic acids · Cofactors/ Flavonoids/Polyketides/Tetrapyrroles
v • d • e
Chelating agents / chelation therapy (V03AC, others)
Iron
Other
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