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Lipoic acid



Lipoic acid
IUPAC name 5-[(3R)-dithiolan-3-yl]pentanoic acid
Other names α-lipoic acid (alpha lipoic acid), thioctic acid
Identifiers
CAS number 62-46-4
PubChem 6112
MeSH Lipoic+acid
SMILES OC(=O)CCCC[C@@H]1CCSS1
Properties
Molecular formula C8H14O2S2
Molar mass 206.328 g/mol
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

Lipoic acid is the organic compound, one enantiomer of which is an essential cofactor for many enzyme complexes. The molecule consists of a carboxylic acid and a cyclic disulfide. Only the R-enantiomer is biologically significant. It is essential for aerobic life and a common dietary supplement. Dihydrolipoic acid is the reduced form of lipoic acid although it is sometimes also called "lipoic acid." "Lipoate" is the conjugate base of lipoic acid, and this form is mainly present at physiological conditions.

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 dehydrogenase (2-OADH) and glycine cleavage complexes (GCV), respectively.[1]

Additional recommended knowledge

Contents

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.[2][3] 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.[4] 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.[5] The configuration found in vivo was later found to be the R-enantiomer.[6]

The first human clinical studies using alpha-lipoic acid (ALA) in the United States were carried out by Fredrick C. Bartter, Burton M. Berkson, and associates from the National Institutes of Health in the 1970’s.[7][8][9] 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. Dr.’s 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).[10]

In addition, because of ALA’s ability to modify gene expression by stabilizing NF kappa B transcription factor, 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 and various oral antioxidants.[11]

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.[12][13] 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.[14] 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.[15] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[16]

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.[17]

Food sources

Lipoic acid is found in a variety of foods, notably kidney, heart and liver meats as well as spinach, broccoli and potatoes. [18][19]

Use as a dietary supplement

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. The relatively good scavenging activity of lipoic acid is due to the strained conformation of the 5-membered ring in the intramolecular disulfide.[20] In cells, lipoic acid can be reduced to dihydrolipoic acid (ΔE= -0.288). Dihydrolipoic acid is able to regenerate (reduce) antioxidants, such as glutathione, vitamin C and vitamin E, maintaining a healthy cellular redox state.[21][22] 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.[23][24] 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.[25] As a result, it may be helpful for people with Alzheimer's disease or Parkinson's disease[citation needed].

Since the early 1990s lipoic acid has been used as a dietary supplement, typically at doses in the range of 100–200 mg/day. In a chronic/carcinogenicity study in rats, it is 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]

On account of its two thiol groups, dihydrolipoic acid has potential for use as a chelating agent in treatment of mercury intoxication. It is particularly suited to this purpose as it can penetrate both the blood-brain barrier and the cell membrane.[citation needed] However, lipoic acid is not commonly used because dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulfonic acid (DMPS) exhibit greater clinical effectiveness. Lipoic acid has not received approval from the U.S. Food and Drug Administration as a chelating agent and questions remain about the possibility that lipoic acid may re-mobilize mercury from peripheral tissue into the central nervous system during administration.

The S-enantiomer

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.[27] 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.[28]

References

  1. ^ Perham RN (2000). "Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions". Annu Rev Biochem 69: 961-1004. PMID 10966480. [1]
  2. ^ Coon MJ and Sligar SG (2003). "Irwin C. Gunsalus, versatile and creative scientist". Biochem Biophys Res Commun 12: 1-23.
  3. ^ O'kane DJ and Gunsalus IC (1948). "Pyruvic Acid Metabolism: A Factor Required for Oxidation by Streptococcus faecalis". J. Bacteriol 56: 499-506.
  4. ^ Parry RJ (1983). "Biosynthesis of some sulfur-containing natural products investigations of the mechanism of carbon-sulfur bond formation". Tetrahedron 39: 1215-1238.
  5. ^ Reed LJ, DeBusk BG, Gunsalus IC, Hornberger CS Jr (1951). "Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase". Science 114 (2952): 93-4. PMID 14854913.
  6. ^ Mislow K and Meluch WC (1956). "The stereochemistry of α-Lipoic acid". J Am Chem Soc 78: 2341-2342.
  7. ^ Berkson, BM. “Thioctic Acid in the Treatment of Poisoning with Alpha amanitin.” Amanita Toxins and Poisonings, 1980. Amanita Toxins and Poisonings, 203 (Heidelberg: International Amanita Symposium, Nov. 1-3, 1978). eds Faulstich, H., Kommerell, B., and Th. Wieland, Verlag Gerhard Witzstrock, Baden-Baden, Koln, New York 1980.
  8. ^ Berkson, B. 1979. Thioctic acid in treatment of hepatotoxic mushroom poisoning (letter). New England Journal of Medicine. 300:371.
  9. ^ Bartter FC, Berkson BM, Gallelli J and Hiranaka P. “Treatment of Four Delayed-Mushroom-Poisoning Patients with Thioctic Acid.” in Amanita Toxins and Poisonings, eds Faulstich, H., Kommerell, B., and T.Wieland, Verlag Gerhard Witzstrock, Baden-Baden, New York 1980.
  10. ^ Berkson BM. “A Conservative Triple Antioxidant Approach to the Treatment of Hepatitis C. Combination of Alpha-Lipoic Acid (Thioctic Acid), Silymarin and Selenium. Three Case Histories.” Medizinische Klinik 94(3), 1999: 84-89.
  11. ^ 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
  12. ^ Milne JL, Wu X, Borgnia MJ, Lengyel JS, Brooks BR, Shi D, Perham RN, Subramaniam S. (2006). "Molecular structure of a 9-MDa icosahedral pyruvate dehydrogenase subcomplex containing the E2 and E3 enzymes using cryoelectron microscopy". J. Biol. Chem 281: 4364-4370. [2]
  13. ^ Murphy GE, Jensen GJ. (2005). "Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes". Structure 13: 1765-1773. [3]
  14. ^ Izard T, Aevarsson A, Allen MD, Westphal AH, Perham RN, de Kok A, Hol WG. (1999). "Principles of quasi-equivalence and Euclidean geometry govern the assembly of cubic and dodecahedral cores of pyruvate dehydrogenase complexes". . Proc. Natl. Acad. Sci. U. S. A 96: 1240-1245. [4]
  15. ^ Machado RS, Clark DP, and Guest JR (1992). "Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain". FEMS Microbiol. Lett 79: 243-248.
  16. ^ 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.
  17. ^ Douce R, Bourguignon J, Neuburger M, and Rebeille F (2001). "The glycine decarboxylase system: a fascinating complex". . Trends Plant Sci 6: 167-176.
  18. ^ Higdon, Jane. Linus Pauling Institute at Oregon State University: Micronutrient Information Center: Lipoic Acid.
  19. ^ Treating Type 2 Diabetes with Dietary Supplements.
  20. ^ Haenen, GRMM and Bast A (1991). "Scavenging of hypochlorous acid by lipoic acid". Biochem Pharmacol 42: 2244-2246.
  21. ^ Biewenga GP Haenen GRMM Bast A (1997). "The pharmacology of the antioxidant lipoic acid.". Gen Pharmacol 29: 315-331.
  22. ^ Packer L, Witt EH, and Tritschler HJ (1995). "alpha-Lipoic acid as a biological antioxidant". Free Radic Biol Med 19: 227-250.
  23. ^ 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. PMID.
  24. ^ Packer L, Kraemer K, Rimbach G (2001). "Molecular aspects of lipoic acid in the prevention of diabetes complications". Nutrition 17 (10): 888-95. PMID.
  25. ^ 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.
  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.
  27. ^ 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.
  28. ^ 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. PMID.

Other Reviews

  • Jane Higdon, "Lipoic Acid", Micronutrient Information Center, Linus Pauling Institute


 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Lipoic_acid". A list of authors is available in Wikipedia.
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