Lipoic acid

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Lipoic acid
Identifiers
CAS number [62-46-4]
PubChem 6112
MeSH Lipoic+acid
Properties
Molecular formula C8H14O2S2
Molar mass 206.328
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references
Skeletal formula of dihydrolipoic acid
Skeletal formula of dihydrolipoic acid

Lipoic acid or α-lipoic acid (alpha lipoic acid) has formula C8H14S2O2 and systematic name 5-(1,2-dithiolan-3-yl)pentanoic acid.

Dihydrolipoic acid or reduced lipoic acid has formula C8H16S2O2 and systematic name 6,8-disulfanyloctanoic acid. It is sometimes called lipoic acid.

Thioctic acid and dihydrothioctic acid are synonyms respectively

Lipoate is the unprotonated base and this form is mainly present at physiological conditions

The most likely introductions people have to lipoic acid are studying the pyruvate dehydrogenase complex or considering alpha lipoic acid as a dietary supplement. Lipoate is a critical cofactor for aerobic metabolism, participating in transfer of acyl or methylamine groups in 2-Oxoacid dehydrogenase (2-OADH) and glycine cleavage complexes (GCV) respectively.[1] Since lipoic acid is an essential cofactor for many enzyme complexes, it is essential for aerobic life as we know it.

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.[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 where the synthetic compound designated α-lipoic acid proved to be the correct enantiomer.[5] The configuration found in vivo was later found to be the R-enantiomer.[6]

[edit] Enantiomers

Lipoic acid exists as two enantiomers, the R-enantiomer and the S-enantiomer. Normally only the R-enantiomer of an amino acid is biologically active, but for lipoic acid the S-enantiomer can assist in the reduction of the R-enantiomer when a racemic mixture is given.

[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.[7][8] 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.[9] 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.[10] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms.[11]

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.[12]

[edit] Use as a dietary supplement

Lipoic acid is a redox-active molecule (ΔE= -0.288) capable of thiol-disulfide exchange, giving it antioxidant activity.[13] Lipoic acid was first postulated to be an effective antioxidant when it was found it prevented vitamin C and vitamin E deficiency. It is able to scavenge reactive oxygen species and reduce other metabolites, such as glutathione or vitamins, maintaining a healthy cellular redox state.[14] 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.[15][16] 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. As a result, it may be helpful for people with Alzheimer's disease or Parkinson's disease.

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 GLUT-4s in cells, responsible for glucose uptake, and hence reduce insulin sensitivity.[17]

Very large doses of 6,8-dithiooctanoic acid are themselves toxic. The lowest reported dosage to exhibit toxic side-effects (TDLo) was 0.83 mg/kg (total dose less than 1/20 gram). The oral LD50 for experimental rodents was found to be between 500 and 1000 mg/kg.

On account of its disulfide group, lipoic acid can be used to chelate mercury from those suffering from mercury intoxications. It is particularly suited to this purpose as it can penetrate both the blood-brain barrier and the cell membrane. However, lipoic acid is not commonly used as a first-line treatment for acute heavy-metal intoxication due the the greater clinical effectiveness of the chelating agents Dimercaptosuccinic acid (DMSA) and Dimercapto-propane sulfonate (DMPS). Lipoic acid has not received approval from the 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.

[edit] 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. ^ 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]
  8. ^ Murphy GE, Jensen GJ. (2005). "Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes". Structure 13: 1765-1773.  [3]
  9. ^ 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]
  10. ^ 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. 
  11. ^ 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. 
  12. ^ Douce R, Bourguignon J, Neuburger M, and Rebeille F (2001). "The glycine decarboxylase system: a fascinating complex". . Trends Plant Sci 6: 167-176. 
  13. ^ Singh, R. & GM. Whitesides (1993), "Thiol-disulfide interchange", in Patai S, Rappoport Z, The chemistry of sulphur-containing functional groups (Supplement S ed.), New York: John Wiley and Sons Ltd
  14. ^ Packer L, Witt EH, and Tritschler HJ (1995). "alpha-Lipoic acid as a biological antioxidant". Free Radic Biol Med 19: 227-250. 
  15. ^ 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. 
  16. ^ Packer L, Kraemer K, Rimbach G (2001). "Molecular aspects of lipoic acid in the prevention of diabetes complications". Nutrition 17 (10): 888-95. PMID. 
  17. ^ 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. 

[edit] External links

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