2.02012-05-31 13:52:59 -06002015-09-13 12:56:11 -0600ECMDB01451M2MDB000392Lipoic acidLipoic acid is a vitamin-like antioxidant that acts as a free-radical scavenger. Alpha-lipoic acid is also known as thioctic acid. Lipoic acid contains two thiol groups which may be either oxidized or reduced. The reduced form is known as dihydrolipoic acid (DHLA). Lipoic acid (Delta E= -0.288) is therefore capable of thiol-disulfide exchange, giving it antioxidant activity. Lipoate is a critical cofactor for aerobic metabolism, participating in the transfer of acyl or methylamine groups via the 2-Oxoacid dehydrogenase (2-OADH) or alpha-ketoglutarate dehydrogenase complex. This enzyme catalyzes the conversion of alpha-ketoglutarate to succinyl CoA. This activity results in the catabolism of the branched chain amino acids (leucine, isoleucine and valine). Lipoic acid also participates in the glycine cleavage system(GCV). The glycine cleavage system is a multi-enzyme complex that catalyzes the oxidation of glycine to form 5,10 methylene tetrahydrofolate, an important cofactor in nucleic acid synthesis. Since Lipoic acid is an essential cofactor for many enzyme complexes, it is essential for aerobic life as we know it. 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. 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. (Wikipedia)α-liponateα-liponic acid(+)-a-Lipoate(+)-a-Lipoic acid(+)-alpha-Lipoate(+)-alpha-Lipoic acid(+)-α-Lipoate(+)-α-Lipoic acid(+-)-1,2-Dithiolane-3-pentanoate(+-)-1,2-Dithiolane-3-pentanoic acid(+-)-1,2-Dithiolane-3-valerate(+-)-1,2-Dithiolane-3-valeric acid(R)-1,2-Dithiolane-3-pentanoate(R)-1,2-Dithiolane-3-pentanoic acid(RS)-a-Lipoate(RS)-a-Lipoic acid(RS)-alpha-Lipoate(RS)-alpha-Lipoic acid(RS)-Lipoate(RS)-Lipoic acid(RS)-α-Lipoate(RS)-α-Lipoic acid1,2-Dithiolane-3-pentanoate1,2-Dithiolane-3-pentanoic acid1,2-Dithiolane-3-valerate1,2-Dithiolane-3-valeric acid1,2-Dithiolane-3R-pentanoate1,2-Dithiolane-3R-pentanoic acid5-(1,2-Dithiolan-3-yl)-pentanoate5-(1,2-Dithiolan-3-yl)-pentanoic acid5-(1,2-Dithiolan-3-yl)pentanoate5-(1,2-Dithiolan-3-yl)pentanoic acid5-(1,2-Dithiolan-3-yl)valerate5-(1,2-Dithiolan-3-yl)valeric acid5-(Dithiolan-3-yl)valerate5-(Dithiolan-3-yl)valeric acid5-[3-(1,2-Dithiolanyl)]pentanoate5-[3-(1,2-Dithiolanyl)]pentanoic acid6,8-Dithiooctanoate6,8-Dithiooctanoic acid6,8-Thioctate6,8-Thioctic acid6,8-Thiotate6,8-Thiotic acid6-Thioctate6-Thioctic acid6-Thiotate6-Thiotic acida Lipoatea Lipoic acida-Lipoatea-Lipoic acida-Liponatea-Liponic acida-LiponsaeureAcetate replacing factorAcetate-replacing factorAcetic acid replacing factorAcetic acid-replacing factorAlpha LipoateAlpha Lipoic acidAlpha-LipoateAlpha-Lipoic acidAlpha-LiponateAlpha-Liponic acidAlpha-LiponsaeureBiletanDelta-[3-(1,2-Dithiacyclopentyl)]pentanoateDelta-[3-(1,2-Dithiacyclopentyl)]pentanoic acidDL-1,2-Dithiolane 3-valerateDL-1,2-Dithiolane 3-valeric acidDL-6,8-DithiooctanoateDL-6,8-Dithiooctanoic acidDL-6,8-ThioctateDL-6,8-Thioctic acidDL-6-ThioctateDL-6-Thioctic acidDL-a-LipoateDL-a-Lipoic acidDL-alpha-LipoateDL-alpha-Lipoic acidDl-LipoateDl-Lipoic acidDl-ThioctateDL-Thioctate > 98%Dl-Thioctic acidDL-Thioctic acid > 98%DL-α-LipoateDL-α-Lipoic acidHeparliponLipLipoateLipoic acidLiponateLiponic acidLiposanLipothionProtogen APyruvate oxidation factorPyruvic acid oxidation factorR-LipoateR-Lipoic acidRac-lipoateRac-lipoic acidThioctacidThioctanThioctateThioctate D-formThioctate dl-formThioctic acidThioctic acid D-formThioctic acid dl-formThioctidaseThioctsanThioktsaeureThiooctanoateThiooctanoic acidTioctacidTioctanTioctidasiTioctidasi acetate replacing factorTioctidasi acetic acid replacing factorα Lipoateα Lipoic acidα-Lipoateα-Lipoic acidα-Liponateα-Liponic acidα-Liponsaeureδ-[3-(1,2-Dithiacyclopentyl)]pentanoateδ-[3-(1,2-Dithiacyclopentyl)]pentanoic acidC8H14O2S2206.326206.0435210725-[(3R)-1,2-dithiolan-3-yl]pentanoic acidlipoic acid1077-28-7OC(=O)CCCC[C@@H]1CCSS1InChI=1S/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1AGBQKNBQESQNJD-SSDOTTSWSA-NSolidCytosolExtra-organismMembranePeriplasmlogp2.75logs-2.96solubility2.24e-01 g/lmelting_point60.5 oClogp2.11pka_strongest_acidic4.52iupac5-[(3R)-1,2-dithiolan-3-yl]pentanoic acidaverage_mass206.326mono_mass206.043521072smilesOC(=O)CCCC[C@@H]1CCSS1formulaC8H14O2S2inchiInChI=1S/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1inchikeyAGBQKNBQESQNJD-SSDOTTSWSA-Npolar_surface_area37.3refractivity54.37polarizability21.74rotatable_bond_count5acceptor_count2donor_count1physiological_charge-1formal_charge0Lipoic acid metabolismLipoic acid metabolism starts with caprylic acid being introduced into the cytoplasm however no transporter has been identified yet.
Once caprylic acid is in the cytoplasm, it can either reacts with a holo-acp, through an ATP driven 2-acylglycerophosphoethanolamine acyltransferase / acyl-ACP synthetase resulting in pyrophosphate, AMP and octanoyl-[acp]. The latter compound can also be obtained from palmitate biosynthesis.
Octanoyl-acp interacts with a lipoyl-carrier protein L-lysine through a Octanoyltransferase resulting in a hydrogen ion, a holo-acyl-acp, and a protein N6-0octanoyl) lysine. The latter compound reacts with an S-adenosylmethionine, a sulfurated[sulfur carrier] and a reduced ferredoxin through a lipoate-protein ligase A, resulting in a 5-deoxyadenosine, a L-methionine, an unsulfurated [sulfur carrier], oxidized ferredoxin, and a Protein N6-(lipoyl) lysine.
Caprylic acid can also interact with ATP and a lipoyl-carrier protein-L-lysine through a lipoate-protein ligase A resulting in a amp, pyrophosphate, hydrogen ion, protein N6-(octanoyl)lysine. The latter compound reacts with an S-adenosylmethionine, a sulfurated[sulfur carrier] and a reduced ferredoxin through a lipoate-protein ligase A, resulting in a 5-deoxyadenosine, a L-methionine, an unsulfurated [sulfur carrier], oxidized ferredoxin, and a Protein N6-(lipoyl) lysine.
R-lipoic acid can be absorbed from the environment, as seen in studies by Morris TW. In this pathway the lipoyl-protein ligase LplA utilizes pre-existing lipoate that has been imported from outside the cell, and thus catalyzes a salvage pathway. Lipoic acid interacts with ATP and hydrogen ion through a lipoyl-protein ligase A, resulting in a pyrophosphate and a Lipoyl-AMP (lipoyl-adenylate). This compound then interacts with a lipoyl-carrier protein-L-lysine through a lipoate-protein ligase A resulting a AMP, a hydrogen ion
and a Protein N6-(lipoyl) lysine.
It has been suggested that the conversion of octanoylated-domains to lipoylated ones described in this pathway may be a type of a repair pathway, activated only if the other lipoate biosynthetic pathways are malfunctioning .
PW000770ec00785Metaboliclipoate salvage IPWY0-522Specdb::CMs3089Specdb::CMs31800Specdb::CMs38079Specdb::CMs99686Specdb::CMs100076Specdb::CMs100077Specdb::CMs155727Specdb::NmrOneD1710Specdb::MsMs1580Specdb::MsMs1581Specdb::MsMs1582Specdb::MsMs179469Specdb::MsMs179470Specdb::MsMs179471Specdb::MsMs181797Specdb::MsMs181798Specdb::MsMs181799Specdb::MsMs2236189Specdb::MsMs2237205Specdb::MsMs2238327Specdb::MsMs2239242Specdb::MsMs2308539Specdb::MsMs2308540Specdb::MsMs2308541Specdb::MsMs2654048Specdb::MsMs2654049Specdb::MsMs2654050Specdb::NmrTwoD1651HMDB014518645886C1624116494LIPOIC-ACIDLPALipoic acidKeseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590.21097882Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114.22080510van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25.17765195Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948.18331064Teichert J, Tuemmers T, Achenbach H, Preiss C, Hermann R, Ruus P, Preiss R: Pharmacokinetics of alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease. J Clin Pharmacol. 2005 Mar;45(3):313-28.15703366Arner ES, Nordberg J, Holmgren A: Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase. Biochem Biophys Res Commun. 1996 Aug 5;225(1):268-74.8769129Henriksen EJ, Saengsirisuwan V: Exercise training and antioxidants: relief from oxidative stress and insulin resistance. Exerc Sport Sci Rev. 2003 Apr;31(2):79-84.12715971Loginov AS, Nilova TV, Bendikov EA, Petrakov AV: [Pharmacokinetics of preparations of lipoic acid and their effect on ATP synthesis, processes of microsomal and cytosol oxidation in hepatocytes in liver damage in man] Farmakol Toksikol. 1989 Jul-Aug;52(4):78-82.2509239Baker H, Deangelis B, Baker ER, Hutner SH: A practical assay of lipoate in biologic fluids and liver in health and disease. Free Radic Biol Med. 1998 Sep;25(4-5):473-9.9741583Konrad D: Utilization of the insulin-signaling network in the metabolic actions of alpha-lipoic acid-reduction or oxidation? Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):1032-9.15998258Bruggraber SF, Leung PS, Amano K, Quan C, Kurth MJ, Nantz MH, Benson GD, Van de Water J, Luketic V, Roche TE, Ansari AA, Coppel RL, Gershwin ME: Autoreactivity to lipoate and a conjugated form of lipoate in primary biliary cirrhosis. Gastroenterology. 2003 Dec;125(6):1705-13.14724823Redden PR, Melanson RL, Douglas JA, Dick AJ: Acyloxymethyl acidic drug derivatives: in vitro hydrolytic reactivity. Int J Pharm. 1999 Apr 15;180(2):151-60.10370185Tankova T, Cherninkova S, Koev D: Treatment for diabetic mononeuropathy with alpha-lipoic acid. Int J Clin Pract. 2005 Jun;59(6):645-50.15924591Chevion S, Hofmann M, Ziegler R, Chevion M, Nawroth PP: The antioxidant properties of thioctic acid: characterization by cyclic voltammetry. Biochem Mol Biol Int. 1997 Feb;41(2):317-27.9063572Barbiroli B, Medori R, Tritschler HJ, Klopstock T, Seibel P, Reichmann H, Iotti S, Lodi R, Zaniol P: Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J Neurol. 1995 Jul;242(7):472-7.7595680Burke DG, Chilibeck PD, Parise G, Tarnopolsky MA, Candow DG: Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration. Int J Sport Nutr Exerc Metab. 2003 Sep;13(3):294-302.14669930Haj-Yehia AI, Assaf P, Nassar T, Katzhendler J: Determination of lipoic acid and dihydrolipoic acid in human plasma and urine by high-performance liquid chromatography with fluorimetric detection. J Chromatogr A. 2000 Feb 18;870(1-2):381-8.10722093Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H, Low PA: Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995 Aug;18(8):1160-7.7587852Steinmann B, Gitzelmann R: Strychnine treatment attempted in newborn twins with severe nonketotic hyperglycinemia. Helv Paediatr Acta. 1979;34(6):589-99.541222Lee WJ, Lee IK, Kim HS, Kim YM, Koh EH, Won JC, Han SM, Kim MS, Jo I, Oh GT, Park IS, Youn JH, Park SW, Lee KU, Park JY: Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol. 2005 Dec;25(12):2488-94. Epub 2005 Oct 13.16224049McCormick DB: A trail of research on cofactors: an odyssey with friends. J Nutr. 2000 Feb;130(2S Suppl):323S-330S.10721897Semenova TV, Azhitskii GIu, Sarnatskaia VV, Nikolaev VG: [Effect of various specific agents on the heat stability of human serum albumin] Ukr Biokhim Zh. 1993 Sep-Oct;65(5):26-30.8160293http://hmdb.ca/system/metabolites/msds/000/001/313/original/HMDB01451.pdf?1358462814Lipoate-protein ligase AP32099LPLA_ECOLIlplAhttp://ecmdb.ca/proteins/P32099.xmlOuter membrane protein NP77747OMPN_ECOLIompNhttp://ecmdb.ca/proteins/P77747.xmlOuter membrane pore protein EP02932PHOE_ECOLIphoEhttp://ecmdb.ca/proteins/P02932.xmlOuter membrane protein FP02931OMPF_ECOLIompFhttp://ecmdb.ca/proteins/P02931.xmlOuter membrane protein CP06996OMPC_ECOLIompChttp://ecmdb.ca/proteins/P06996.xmlAdenosine triphosphate + Lipoic acid > Lipoyl-AMP + PyrophosphateR07770RXN-8654Adenosine triphosphate + Lipoic acid <> Pyrophosphate + Lipoyl-AMPR07770Hydrogen ion + Lipoic acid + Adenosine triphosphate > Lipoyl-AMP + PyrophosphateRXN-8654(R)-lipoic acid + Adenosine triphosphate + Hydrogen ion + Lipoic acid > Pyrophosphate + Lipoyl-AMP + Lipoyl-AMPPW_R003559