Lipoic acid

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ImageFile = Lipoic-acid-2D-skeletal.png ImageSize =
ImageFile1 = Lipoic-acid-3D-vdW.png IUPACName = 5- [(3"R")-dithiolan-3-yl] pentanoic acid
OtherNames = α-lipoic acid (alpha lipoic acid), thioctic acid, 6,8-dithiooctanoic acid
Section1 = Chembox Identifiers
CASNo = 62-46-4
PubChem = 6112
SMILES = OC(=O)CCCC [C@@H] 1CCSS1
MeSHName = Lipoic+acid
Section2 = Chembox Properties
Formula = C₈H₁₄O₂S₂
MolarMass = 206.328 g/mol
Appearance =
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Section3 = Chembox Hazards
Solubility =
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Section4 = Chembox Pharmacology
Bioavail = 30% (oral) [cite journal |author=Teichert J, Hermann R, Ruus P, Preiss R |title=Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers |journal=J Clin Pharmacol |volume=43 |issue=11 |pages=1257–67 |year=2003 |month=Nov |pmid=14551180 |doi=10.1177/0091270003258654 |url=]

Lipoic acid is an 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. [cite journal | author=Perham RN | title=Swinging arms and swinging domains in multifunctional enzymes: catalytic machines for multistep reactions | journal=Annu Rev Biochem | year=2000 | pages=961–1004 | volume=69 | issue=|pmid=10966480 | doi = 10.1146/annurev.biochem.69.1.961 [http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.biochem.69.1.961] ]

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. [cite journal | author=Coon MJ and Sligar SG| title=Irwin C. Gunsalus, versatile and creative scientist | journal=Biochem Biophys Res Commun | year=2003 | pages=1–23 | volume=12 | issue= | id= | doi=10.1016/0006-291X(63)90404-2 ] [cite journal | author=O'kane DJ and Gunsalus IC| title=Pyruvic Acid Metabolism: A Factor Required for Oxidation by Streptococcus faecalis | journal=J. Bacteriol | year=1948 | pages=499–506 | volume=56 | issue= | id= ] 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. [cite journal | author=Parry RJ| title=Biosynthesis of some sulfur-containing natural products investigations of the mechanism of carbon-sulfur bond formation | journal=Tetrahedron | year=1983 | pages=1215–1238 | volume=39 | issue=|id= | doi = 10.1016/S0040-4020(01)91887-3] 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. [cite journal | author=Reed LJ, DeBusk BG, Gunsalus IC, Hornberger CS Jr | title=Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase | journal=Science | year=1951 | pages=93–4 | volume=114 | issue=2952 | pmid=14854913 | doi = 10.1126/science.114.2952.93] The configuration found "in vivo" was later found to be the R-enantiomer. [cite journal | author=Mislow K and Meluch WC| title=The stereochemistry of α-Lipoic acid | journal=J Am Chem Soc | year=1956 | pages=2341–2342 | volume=78 | issue= | id=| doi=10.1021/ja01591a087]

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. [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.] [Berkson, B. 1979. Thioctic acid in treatment of hepatotoxic mushroom poisoning (letter). New England Journal of Medicine. 300:371.] [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.] 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). [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.]

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, low dose naltrexone (LDN), and various oral antioxidants. [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] 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. [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]

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. [cite journal | author= Milne JL, Wu X, Borgnia MJ, Lengyel JS, Brooks BR, Shi D, Perham RN, Subramaniam S. | title= Molecular structure of a 9-MDa icosahedral pyruvate dehydrogenase subcomplex containing the E2 and E3 enzymes using cryoelectron microscopy | journal= J. Biol. Chem | year=2006 | pages=4364–4370 | volume=281 | issue= | id= | doi = 10.1074/jbc.M504363200 | pmid= 16308322 [http://www.jbc.org/cgi/content/full/281/7/4364] ] [cite journal | author= Murphy GE, Jensen GJ. | title= Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes | journal= Structure | year=2005 | pages=1765–1773 | volume=13 | issue= | id= | doi = 10.1016/j.str.2005.08.016 [http://www.structure.org/content/article/abstract?uid=PIIS096921260500359X] ] 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. [cite journal | author= Izard T, Aevarsson A, Allen MD, Westphal AH, Perham RN, de Kok A, Hol WG.| title= Principles of quasi-equivalence and Euclidean geometry govern the assembly of cubic and dodecahedral cores of pyruvate dehydrogenase complexes | journal=. Proc. Natl. Acad. Sci. U. S. A | year=1999 | pages=1240–1245| volume=96 | issue= | id= | doi = 10.1073/pnas.96.4.1240| pmid= 9990008 [http://www.pnas.org/cgi/content/abstract/96/4/1240] ] 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. [cite journal | author= Machado RS, Clark DP, and Guest JR| title= Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain | journal= FEMS Microbiol. Lett | year=1992 | pages=243–248 | volume=79 | issue= | id=| doi= 10.1111/j.1574-6968.1992.tb05710.x] The lipoyl domains within a given complex are homogenous, while at least two major clusters of lipoyl domains exist in sequenced organisms. [cite journal | author= Omelchenko MV, Makarova KS, and Koonin EV|title= Recurrent intragenomic recombination leading to sequence homogenization during the evolution of the lipoyl-binding domain | journal=J FEMS Microbiol. Lett | year=2002 | pages=255–260 | volume=209 | issue= | id=|doi= 10.1111/j.1574-6968.2002.tb11140.x]

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. [cite journal | author=Douce R, Bourguignon J, Neuburger M, and Rebeille F | title= The glycine decarboxylase system: a fascinating complex | journal=. Trends Plant Sci | year=2001 | pages=167–176| volume=6 | issue= | id= | doi = 10.1016/S1360-1385(01)01892-1]

Food sources

Lipoic acid is found in a variety of foods, notably kidney, heart and liver meats as well as spinach, broccoli and potatoes. It is noted that: "Although LA is found in a wide variety of foods from plant and animal sources, quantitative information on the LA or lipoyllysine content of food is limited and published databases are lacking." [Cite web| last=Higdon | first=Jane | title=Linus Pauling Institute at Oregon State University: Micronutrient Information Center: Lipoic Acid | url=http://lpi.oregonstate.edu/infocenter/othernuts/la/index.html#food_source | access-date=2007-04-06] [Cite web | url=http://nccam.nih.gov/health/diabetes/#alpha | title=Treating Type 2 Diabetes with Dietary Supplements | access-date=2007-04-06]

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 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. [cite journal | author= Haenen, GRMM and Bast A | title= Scavenging of hypochlorous acid by lipoic acid | journal= Biochem Pharmacol | year=1991 | pages=2244–2246| volume=42 | issue= | id= | doi = 10.1016/0006-2952(91)90363-A] 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, maintaining a healthy cellular redox state. [cite journal | author= Biewenga GP Haenen GRMM Bast A | title= The pharmacology of the antioxidant lipoic acid | journal= Gen Pharmacol | year=1997 | pages=315–331| volume=29 | issue= | id=] [cite journal | author= Packer L, Witt EH, and Tritschler HJ | title= alpha-Lipoic acid as a biological antioxidant | journal=Free Radic Biol Med | year=1995 | pages=227–250| volume=19 | issue= | doi = 10.1016/0891-5849(95)00017-R] 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. [cite journal | author=Henriksen EJ | title=Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes | journal=Free Radic Biol Med | year=2006 | pages=3–12 | volume=40 | issue=1| doi = 10.1016/j.freeradbiomed.2005.04.002] [cite journal | author=Packer L, Kraemer K, Rimbach G | title=Molecular aspects of lipoic acid in the prevention of diabetes complications | journal=Nutrition | year=2001 | pages=888–95 | volume=17 | issue=10| doi = 10.1016/S0899-9007(01)00658-X] 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. [cite journal
title= Delaying the Mitochondrial Decay of Aging with Acetylcarnitine
author = [http://www.bruceames.org/n/about.php B. N. Ames] , J. Liu
journal= Ann. N.Y. Acad. Sci.
volume= 1033
pages= 108–116
year= 2004
doi= 10.1196/annals.1320.010
pmid= 15591008] As a result, it may be helpful for people with Alzheimer's disease or Parkinson's disease. [cite journal
title= Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats
author = [http://bio.utsa.edu/ntfaculty/aliev.html 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, [http://bio.utsa.edu/faculty/perry.html G. Perry] , [http://www.bruceames.org/n/about.php B. N. Ames]
journal= J. Cell. Mol. Med.
volume= Epub ahead of print
year= 2008
doi= 10.1111/j.1582-4934.2008.00324.x
pages = 080329002216155] 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. [cite journal | author= Cremer DR Rabeler R Roberts A Lynch B | title= -term safety of alpha-lipoic acid (ALA) consumption: A 2-year study | journal= Long Regul Toxicol Pharmacol| year=2006 | pages=193–201| volume=46 | issue= | id= | doi= 10.1016/j.yrtph.2006.06.003]

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. [cite journal | author= Biewenga GP Haenen GRMM Groen BH Biewenga JE Van Grondelle R and Bast A | title= Combined non-enzymatic and enzymatic reduction favors bioactivation of racemic lipoic acid: an advantage of a racemic drug? | journal= Chirality | year=1997 | pages=362–366 | volume=9 | issue= | id= | doi = 10.1002/(SICI)1520-636X(1997)9:4<362::AID-CHIR8>3.0.CO;2-F] 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. [cite journal | author=Loffelhardt S, Bonaventura C, Locher M, Borbe HO, Bisswanger H | title=Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex | journal=Biochem Pharmacol | year=1995 | pages=637–46 | volume=50 | issue=5| doi = 10.1016/0006-2952(95)00175-Y]

Use as a chelator

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. [cite journal
title= Neuroprotection by the metabolic antioxidant alpha-lipoic acid
author = Packer L, Tritschler HJ, Wessel K.
journal= Free Radic Biol Med.
volume= 22(1-2)
pages= 359–78
year= 1997
doi= 10.1016/S0891-5849(96)00269-9] Other chelators such as dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulfonic acid (DMPS) are unable to cross the brain-blood barrier and to remove mercury from the brain [cite journal
first = James
last = Rooney
year = 2007
title = The role of thiols, dithiols, nutritional factors andinteracting ligands in the toxicology of mercury
journal = Toxicology
volume = 234
pages = 145–156
doi = 10.1016/j.tox.2007.02.016 ] [cite journal
first = GianPaolo
last = Guzzi
coauthors = Caterina A.M. La Porta
year = 2008
title = Molecular mechanisms triggered by mercury
journal = Toxicology
volume = 244
pages = 1–12
doi = 10.1016/j.tox.2007.11.002 ] . 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.

References

Other Reviews

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