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| StdInChIKey = AGBQKNBQESQNJD-SSDOTTSWSA-N
| CASNo1_Ref = {{cascite|correct|CAS}}
| CASNo1 = 1200-22-2
| CASNo1_Comment = (''R'')
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 1077-28-7
| CASNo_Comment = (racemate)
| UNII1_Ref = {{fdacite|correct|FDA}}
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| Appearance = Yellow needle-like crystals
| Solubility = Very Slightly Soluble(0.24 g/L)<ref name="pubmed">{{cite web |url= https://pubchem.ncbi.nlm.nih.gov/compound/thioctic_acid#section=Physical-Description|title=Lipoic Acid |author=<!--Not stated--> |website=Pubmed |publisher=NCBI |access-date=October 18, 2018 }}</ref>
| SolubleOther = Soluble
| Solvent = ethanol 50 mg/mL
| Density =
| MeltingPtC = 60-62
| BoilingPtC =
}}
|Section7={{Chembox Hazards
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}}
'''Lipoic acid''' ('''LA'''), also known as '''
==Physical and chemical properties==
Lipoic acid contains two sulfur atoms connected by a [[disulfide bond]] in the 1,2-[[dithiolane]] ring. It also carries a carboxylic acid group. It is considered to be oxidized relative to its acyclic relative dihydrolipoic acid, in which each sulfur exists as a thiol.<ref name=lpi/> It is a yellow solid.
For use in [[dietary supplement]] materials and [[compounding]] pharmacies, the [[United States Pharmacopeia|USP]] established an official monograph for R/S-LA.<ref>{{cite book |title= USP32-NF27 |page= 1042|title-link= United States Pharmacopeia}}</ref><ref>{{cite journal |title=Unavailable First-Time Official USP Reference Standards |author=<!--Staff writer(s); no by-line.--> |journal=Pharmacopeial Forum |volume=35 |page=26 |publisher=USP |date=February 2009 |url=https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/pf-legacy-pdf/pf-2009_vol-35.pdf |language=en |access-date=13 January 2023 |url-status=live |archive-url=https://web.archive.org/web/20220305141903/https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/pf-legacy-pdf/pf-2009_vol-35.pdf |archive-date=5 March 2022 }}</ref>
==Biological function==
Lipoic acid is a cofactor for five enzymes or classes of enzymes: [[pyruvate dehydrogenase]],
HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are targets of the reduced form (open
===Biosynthesis and attachment===
Most endogenously produced RLA are not "free" because octanoic acid, the precursor to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is covalently attached by an amide bond to a terminal lysine residue of the enzyme's lipoyl domains.
The precursor to lipoic acid, [[octanoic acid]], is made via [[fatty acid biosynthesis]] in the form of octanoyl-[[acyl carrier protein]].<ref name=lpi/> In [[eukaryotes]], a second fatty acid biosynthetic pathway in [[mitochondria]] is used for this purpose.<ref name=lpi/> The octanoate is transferred as a thioester of [[acyl carrier protein]] from [[fatty acid biosynthesis]] to an [[amide]] of the lipoyl domain protein by an [[enzyme]] called an octanoyltransferase.<ref name=lpi/> Two hydrogens of octanoate are replaced with sulfur groups via a [[radical SAM]] mechanism, by [[lipoyl synthase]].<ref name=lpi/> As a result, lipoic acid is synthesized attached to proteins and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by action of the enzyme lipoamidase.<ref>{{cite journal |last1= Jiang |first1= Y |last2= Cronan |first2= JE |year= 2005 |title= Expression cloning and demonstration of ''Enterococcus faecalis'' lipoamidase (pyruvate dehydrogenase inactivase) as a Ser-Ser-Lys triad amidohydrolase |journal= [[Journal of Biological Chemistry]] |volume= 280 |issue= 3 |pages= 2244–56 |pmid= 15528186 |doi= 10.1074/jbc.M408612200 |doi-access= free }}</ref> Free lipoate can be used by some organisms as an enzyme called [[lipoate protein ligase]] that attaches it covalently to the correct protein. The [[ligase]] activity of this [[enzyme]] requires [[Adenosine triphosphate|ATP]].<ref>{{cite book |last1= Cronan |first1= JE |title= Function, attachment and synthesis of lipoic acid in ''Escherichia coli'' |last2= Zhao |first2= X |last3= Jiang |first3= Y |year= 2005 |series= Advances in Microbial Physiology |volume= 50 |pages= 103–46 |pmid= 16221579 |doi= 10.1016/S0065-2911(05)50003-1 |isbn= 9780120277506 |editor-first= RK |editor-last= Poole}}
</ref>
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===Cellular transport===
Along with [[sodium]] and the vitamins [[biotin]] (B7) and [[pantothenic acid]] (B5), lipoic acid enters cells through the [[Sodium-dependent multivitamin transporter|SMVT]] (sodium-dependent multivitamin transporter). Each of the compounds transported by the SMVT is competitive with the others. For example research has shown that increasing intake of lipoic acid<ref>{{Cite journal|pmid = 9278559|year = 1997|last1 = Zempleni|first1 = J.|last2 = Trusty|first2 = T. A.|last3 = Mock|first3 = D. M.|title = Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver|journal = The Journal of Nutrition|volume = 127|issue = 9|pages = 1776–81|doi = 10.1093/jn/127.9.1776|doi-access = free}}</ref> or pantothenic acid<ref>{{Cite journal|pmid = 23578027|year = 2013|last1 = Chirapu|first1 = S. R.|last2 = Rotter|first2 = C. J.|last3 = Miller|first3 = E. L.|last4 = Varma|first4 = M. V.|last5 = Dow|first5 = R. L.|last6 = Finn|first6 = M. G.|title = High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid|journal = Current Topics in Medicinal Chemistry|volume = 13|issue = 7|pages = 837–42|doi = 10.2174/1568026611313070006}}</ref> reduces the uptake of biotin and/or the activities of biotin-dependent enzymes.
===Enzymatic activity===
Lipoic acid is a [[Cofactor (biochemistry)|cofactor]] for at least five [[enzyme]] systems.<ref name=lpi/> Two of these are in the [[citric acid cycle]] through which many organisms turn nutrients into energy. Lipoylated [[enzymes]] have lipoic acid attached to them covalently. The lipoyl group transfers [[acyl]] groups in [[2-oxoacid dehydrogenase]] complexes, and [[methylamine]] group in the [[glycine cleavage complex]] or [[glycine dehydrogenase]].<ref name=lpi/>
Lipoic acid is the cofactor of the following enzymes in humans:<ref>{{Cite journal |last1=Mayr |first1=Johannes A. |last2=Feichtinger |first2=René G. |last3=Tort |first3=Frederic |last4=Ribes |first4=Antonia |last5=Sperl |first5=Wolfgang |date=2014 |title=Lipoic acid biosynthesis defects |url=https://onlinelibrary.wiley.com/doi/10.1007/s10545-014-9705-8 |journal=Journal of Inherited Metabolic Disease |language=en |volume=37 |issue=4 |pages=553–563 |doi=10.1007/s10545-014-9705-8 |pmid=24777537 |s2cid=27408101 |issn=0141-8955}}</ref><ref>{{Cite journal |last1=Solmonson |first1=Ashley |last2=DeBerardinis |first2=Ralph J. |date=2018 |title=Lipoic acid metabolism and mitochondrial redox regulation |journal=Journal of Biological Chemistry |language=en |volume=293 |issue=20 |pages=7522–7530 |doi=10.1074/jbc.TM117.000259 |doi-access=free |pmc=5961061 |pmid=29191830}}</ref><ref>{{Cite journal |last1=Nemeria |first1=Natalia S. |last2=Nagy |first2=Balint |last3=Sanchez |first3=Roberto |last4=Zhang |first4=Xu |last5=Leandro |first5=João |last6=Ambrus |first6=Attila |last7=Houten |first7=Sander M. |last8=Jordan |first8=Frank |date=2022-07-26 |title=Functional Versatility of the Human 2-Oxoadipate Dehydrogenase in the L-Lysine Degradation Pathway toward Its Non-Cognate Substrate 2-Oxopimelic Acid |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=15 |pages=8213 |doi=10.3390/ijms23158213 |doi-access=free |issn=1422-0067 |pmc=9367764 |pmid=35897808}}</ref>
{| class="wikitable"
* the [[pyruvate dehydrogenase complex]]▼
|+
!EC-number
* the [[branched chain oxoacid dehydrogenase|branched-chain oxoacid dehydrogenase]] (BCDH) complex▼
!Enzyme
!Gene
!Multienzyme complex
!Type of metabolism
|-
|[[Enzyme Commission number|EC]] [https://enzyme.expasy.org/EC/2.3.1.12 2.3.1.12]
|[[dihydrolipoyl transacetylase]] (E2)
|[[DLAT]]
| rowspan="2" |[[energy metabolism]]
|-
| rowspan="2" |EC [https://enzyme.expasy.org/EC/2.3.1.61 2.3.1.61]
| rowspan="2" |[[Dihydrolipoyllysine-residue succinyltransferase|dihydrolipoyl succinyltransferase]] (E2)
| rowspan="2" |[[DLST]]
|[[oxoglutarate dehydrogenase complex]] (OGDC)
|-
|[[2-oxoadipate dehydrogenase complex]] (OADHC)
| rowspan="3" |[[amino acid metabolism]]
|-
|EC [https://enzyme.expasy.org/EC/2.3.1.168 2.3.1.168]
|[[dihydrolipoyl transacylase]] (E2)
|[[DBT (gene)|DBT]]
▲
|-
|
|[[GCSH|H-protein]]
|[[GCSH]]
|[[glycine cleavage system]] (GCS)
|}
The most-studied of these is the pyruvate dehydrogenase complex.<ref name=lpi/> 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.<ref name=lpi/> 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.<ref>{{cite journal |last1= Machado |first1= RS |last2= Clark |first2= DP |last3= Guest |first3= JR |title= Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain |journal= FEMS Microbiology Letters |year= 1992 |pages= 243–8 |volume= 79 |issue= 1–3 |doi= 10.1111/j.1574-6968.1992.tb14047.x |pmid= 1478460|doi-access= free }}</ref>
Lipoic acid serves as co-factor to the [[acetoin dehydrogenase]] complex catalyzing the conversion of [[acetoin]] (3-hydroxy-2-butanone) to acetaldehyde and [[acetyl coenzyme A]].<ref name=lpi/>
The [[glycine cleavage system]] differs from the other complexes, and has a different nomenclature.<ref name=lpi/> In this system, 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 to synthesize [[serine]] from [[glycine]]. This system is part of plant [[photorespiration]].<ref>{{cite journal |last1= Douce |first1= R |last2= Bourguignon |first2= J |last3= Neuburger |first3= M |last4= Rebeille |first4= F |title= The glycine decarboxylase system: A fascinating complex |journal= [[Trends (journals)|Trends in Plant Science]] |year= 2001 |pages= 167–76 |volume= 6 |issue= 4 |doi= 10.1016/S1360-1385(01)01892-1 |pmid= 11286922|bibcode= 2001TPS.....6..167D }}</ref>
===Biological sources and degradation===
Lipoic acid is present in many foods in which it is bound to lysine in proteins,<ref name=lpi/> but slightly more so in kidney, heart, liver, spinach, broccoli, and yeast extract.<ref>{{cite journal |last1= Durrani |first1= AI |last2= Schwartz |first2= H |last3= Nagl |first3= M |last4= Sontag |first4= G |title= Determination of free [alpha]-lipoic acid in foodstuffs by HPLC coupled with CEAD and ESI-MS |journal= [[Food Chemistry (journal)|Food Chemistry]] |date= October 2010 |pages= 38329–36 |volume= 120 |issue= 4 |doi= 10.1016/j.foodchem.2009.11.045}}</ref> Naturally occurring lipoic acid is always covalently bound and not readily available from dietary sources.<ref name=lpi/> In addition, the amount of lipoic acid present in dietary sources is low. For instance, the purification of lipoic acid to determine its structure used an estimated 10 tons of liver residue, which yielded 30 mg of lipoic acid.<ref>{{cite journal |last= Reed |first= LJ |title= A trail of research from lipoic acid to alpha-keto acid dehydrogenase complexes |journal= [[Journal of Biological Chemistry]] |date= October 2001 |pages= 38329–36 |volume= 276 |issue= 42 |pmid= 11477096 |doi= 10.1074/jbc.R100026200 |doi-access= free }}</ref> As a result, all lipoic acid available as a supplement is chemically synthesized.
Baseline levels (prior to supplementation) of RLA and R-DHLA have not been detected in human plasma.<ref>{{cite journal | doi = 10.1016/0928-0987(95)00045-3 |last1= Hermann |first1= R |year= 1996 |title= Enantioselective pharmacokinetics and bioavailability of different racemic formulations in healthy volunteers |journal= [[European Journal of Pharmaceutical Sciences]] |volume= 4 |issue= 3 |pages= 167–74 |last2= Niebch |first2= G |last3= Borbe |first3= HO |last4= Fieger |first4= H |last5= Ruus |first5= P |last6= Nowak |first6= H |last7= Riethmuller-Winzen |first7= H |last8= Peukert |first8= M |last9= Blume |first9= H |display-authors= 4}}</ref> RLA has been detected at 12.3−43.1 ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6 ng/mL and <1-38.2 ng/mL using [[subtilisin]] and [[alcalase]], respectively.<ref>{{cite book |doi= 10.1016/S0076-6879(97)79019-0 |pmid= 9211267 |last1= Teichert |first1= J |last2= Preiss |first2= R |
Digestive proteolytic enzymes cleave the R-lipoyllysine residue from the mitochondrial enzyme complexes derived from food but are unable to cleave the lipoic acid-<small>L</small>-[[lysine]] amide bond.<ref>{{cite journal |pmid= 9378235 |last1= Biewenga |first1= GP |last2= Haenen |first2= GR |last3= Bast |first3= A |title= The pharmacology of the antioxidant lipoic acid |journal= General Pharmacology |volume= 29 |issue= 3 |date= September 1997 |pages=315–31 |doi= 10.1016/S0306-3623(96)00474-0}}</ref> Both synthetic lipoamide and (''R'')-lipoyl-<small>L</small>-lysine are rapidly cleaved by serum lipoamidases, which release free (''R'')-lipoic acid and either <small>L</small>-lysine or ammonia.<ref name=lpi/> Little is known about the degradation and utilization of aliphatic sulfides such as lipoic acid, except for [[cysteine]].<ref name=lpi/>
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=== Combined malonic and methylmalonic aciduria (CMAMMA) ===
In the metabolic disease [[combined malonic and methylmalonic aciduria]] (CMAMMA) due to [[ACSF3]] deficiency, mitochondrial fatty acid synthesis (mtFASII), which is the precursor reaction of lipoic acid biosynthesis, is impaired.<ref>{{Cite journal |
==Chemical synthesis==
[[Image:(R)-Liponic Acid Structural Formula V.1.svg|200px|R-isomer]] [[Image:(S)-Liponic Acid Structural Formula V.1.svg|200px|S-isomer]]
SLA did not exist prior to chemical synthesis in 1952.<ref>{{cite journal |last1= Hornberger |first1= CS |last2= Heitmiller |first2= RF |last3= Gunsalus |first3= IC |last4= Schnakenberg |first4= GHF |last5= Reed |first5= LJ |display-authors= 4 |title= Synthesis of DL—lipoic acid |journal= [[Journal of the American Chemical Society]] |volume= 75 |issue= 6 |pages= 1273–7 |year= 1953 |doi= 10.1021/ja01102a003}}</ref><ref>{{cite journal |last1= Hornberger |first1= CS |last2= Heitmiller |first2= RF |last3= Gunsalus |first3= IC |last4= Schnakenberg |first4= GHF |last5= Reed |first5= LJ |display-authors= 4 |title= Synthetic preparation of lipoic acid |journal= [[Journal of the American Chemical Society]] |volume= 74 |issue= 9 |page= 2382 |year= 1952 |doi= 10.1021/ja01129a511}}</ref> SLA is produced in equal amounts with RLA during achiral manufacturing processes. The racemic form was more widely used clinically in Europe and Japan in the 1950s to 1960s despite the early recognition that the various forms of LA are not bioequivalent.<ref name="Kleeman" /> The first synthetic procedures appeared for RLA and SLA in the mid-1950s.<ref>{{cite journal |pmid= 13294188 |last1= Fontanella |first1= L |title= Preparation of optical antipodes of alpha-lipoic acid |journal= Il Farmaco; Edizione Scientifica |volume= 10 |issue= 12 |year= 1955 |pages= 1043–5}}</ref><ref>{{cite journal |last1= Walton |first1= E |last2= Wagner |first2= AF |last3= Bachelor |first3= FW |last4= Peterson |first4= LH |last5= Holly |first5= FW |last6= Folkers |first6= K |display-authors= 4 |title= Synthesis of (+)-lipoic acid and its optical antipode |journal= [[Journal of the American Chemical Society]] |volume= 77 |issue= 19 |pages= 5144–9 |year= 1955 |doi= 10.1021/ja01624a057 }}</ref><ref>{{cite journal |last1= Acker |first1= DS |last2= Wayne |first2= WJ |title= Optically active and radioactive
==Pharmacology==
===Pharmacokinetics===
A 2007 human [[pharmacokinetic]] study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.<ref name="ReferenceB">{{cite journal |last1= Carlson |first1= DA |last2= Smith |first2= AR |last3= Fischer |first3= SJ |last4= Young |first4= KL |last5= Packer |first5= L |display-authors= 4 |title= The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects |journal= Alternative Medicine Review |volume= 12 |issue= 4 |date= December 2007 |pages= 343–51 |pmid= 18069903 |url= http://www.altmedrev.com/publications/12/4/343.pdf |access-date= 2014-07-06 |archive-date= 2017-08-08 |archive-url= https://web.archive.org/web/20170808231646/http://altmedrev.com/publications/12/4/343.pdf |url-status= dead }}</ref> Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.<ref name="ReferenceB"/>
The various forms of LA are not bioequivalent.<ref name="Kleeman">{{cite conference |last1= Kleeman |first1= A |last2= Borbe |first2= HO |last3= Ulrich |first3= H |chapter= Thioctic Acid-Lipoic Acid |title= Thioctsäure: Neue Biochemische, Pharmakologische und Klinische Erkenntnisse zur Thioctsäure |trans-title= Thioctic Acid. New Biochemistry, Pharmacology and Findings from Clinical Practice with Thioctic Acid |pages= 11–26 |editor1-last= Borbe |editor1-first= HO |editor2-last= Ulrich |editor2-first= H |conference= Symposium at Wiesbaden, DE, 16–18 February 1989 |date= 1991 |location= Frankfurt, DE |publisher= Verlag |isbn= 9783891191255}}</ref>{{psi|date=December 2017}} Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.<ref name="ReferenceB"/>
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==Clinical research==
According to the [[American Cancer Society]] as of 2013, "there is no reliable scientific evidence at this time that lipoic acid prevents the development or spread of cancer".<ref>{{cite web|url=http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/lipoic-acid|title=Lipoic Acid|date=November 2008|publisher=[[American Cancer Society]]|access-date=5 October 2013|archive-date=24 April 2015|archive-url=https://web.archive.org/web/20150424110743/http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/lipoic-acid|url-status=dead}}</ref> As of 2015, intravenously administered ALA is unapproved anywhere in the world except Germany for [[diabetic neuropathy]], but has been proven reasonably safe and effective
==Other lipoic acids==
* [[
==See also==
* [[Aminolevulinic acid]]
==References==
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==External links==
* {{Commons category-inline}}
{{Enzyme cofactors}}
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[[Category:Carboxylic acids]]
[[Category:Cofactors]]
[[Category:Drugs developed by Eli Lilly and Company
[[Category:Organic disulfides]]
[[Category:1,2-Dithiolanes]]
[[Category:Anti-aging substances]]
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