Lipoic acid: Difference between revisions

| CASNo1 = 1200-22-2

| CASNo = 1077-28-7

| SolubleOther = Soluble

| BoilingPtC =

'''Lipoic acid''' ('''LA'''), also known as '''αあるふぁ-lipoic acid''', '''alpha-lipoic acid''' ('''ALA''') and '''thioctic acid''', is an [[organosulfur compound]] derived from [[caprylic acid]] (octanoic acid).<ref name="lpi">{{cite web |title=Lipoic acid |url=https://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid |publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis |access-date=5 November 2019 |date=1 January 2019}}</ref> ALA, which is made in animals normally, and is essential for [[aerobic metabolism]]. It is also manufactured and is available as a [[dietary supplement]] inor some countries where it is marketed as an [[antioxidant]], and is available as a [[pharmaceutical drug]] in othersome countries. '''Lipoate''' is the [[conjugate base]] of lipoic acid, and the most prevalent form of LA under physiological conditions.<ref name=lpi/> Only the (''R'')-(+)-[[enantiomer]] (RLA) exists in nature. RLA is an essential [[Cofactor (biochemistry)|cofactor]] of many processes.<ref name=lpi/>

The carbon atom at C6 is [[chirality (chemistry)|chiral]] and the molecule exists as two [[enantiomers]] (''R'')-(+)-lipoic acid (RLA) andoccurs naturally, but (''S'')-(-)-lipoic acid (SLA) andhas asbeen a [[racemic mixture]] (''R''/''S'')-lipoic acid (R/S-LA)synthesized.

Lipoic acid is a cofactor for five enzymes or classes of enzymes: [[pyruvate dehydrogenase]], [[Oxoglutarate dehydrogenase complex|αあるふぁ-ketoglutarate dehydrogenase]], the [[glycine cleavage system]], branched[[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain alpha-keto acid dehydrogenase]], and the αあるふぁ-oxo(keto)adipate dehydrogenase. The first two are critical to the [[citric acid cycle]]. The GCS regulates [[glycine]] concentrations.<ref>{{cite journal |doi=10.3389/fgene.2020.00510|doi-access=free |title=Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes |year=2020 |last1=Cronan |first1=John E. |journal=Frontiers in Genetics |volume=11 |page=510 |pmid=32508887 |pmc=7253636 }}</ref>

HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are targets of the reduced form (open disulfidedithiol) of (''R'')-lipoic acid. <ref>{{cite journal | url=https://doi.org/10.1038/s41467-023-39151-8 | doi=10.1038/s41467-023-39151-8 | title=Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid | date=2023 | last1=Lechner | first1=Severin | last2=Steimbach | first2=Raphael R. | last3=Wang | first3=Longlong | last4=Deline | first4=Marshall L. | last5=Chang | first5=Yun-Chien | last6=Fromme | first6=Tobias | last7=Klingenspor | first7=Martin | last8=Matthias | first8=Patrick | last9=Miller | first9=Aubry K. | last10=Médard | first10=Guillaume | last11=Kuster | first11=Bernhard | journal=Nature Communications | volume=14 | issue=1 | page=3548 | pmid=37322067 | pmc=10272112 | bibcode=2023NatCo..14.3548L }}</ref>

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 [[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>

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 |last1=Levtova |first1=Alina |last2=Waters |first2=Paula J. |last3=Buhas |first3=Daniela |last4=Lévesque |first4=Sébastien |last5=Auray-Blais |first5=Christiane |author-link5=Christiane Auray-Blais |last6=Clarke |first6=Joe T.R. |last7=Laframboise |first7=Rachel |last8=Maranda |first8=Bruno |last9=Mitchell |first9=Grant A. |last10=Brunel-Guitton |first10=Catherine |last11=Braverman |first11=Nancy E. |date=2019 |title=Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort |url=https://onlinelibrary.wiley.com/doi/10.1002/jimd.12032 |journal=Journal of Inherited Metabolic Disease |language=en |volume=42 |issue=1 |pages=107–116 |doi=10.1002/jimd.12032 |issn=0141-8955 |pmid=30740739 |s2cid=73436689 |issn=0141-8955}}</ref><ref name=":0">{{Cite journal |last1=Wehbe |first1=Zeinab |last2=Behringer |first2=Sidney |last3=Alatibi |first3=Khaled |last4=Watkins |first4=David |last5=Rosenblatt |first5=David |last6=Spiekerkoetter |first6=Ute |last7=Tucci |first7=Sara |date=2019-11-01 |title=The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism |url=https://www.sciencedirect.com/science/article/pii/S1388198119301349 |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1864 |issue=11 |pages=1629–1643 |doi=10.1016/j.bbalip.2019.07.012 |pmid=31376476 |s2cid=199404906 |issn=1388-1981}}</ref> The result is a reduced [[Post-translational modification#PTMs involving addition of functional groups|lipoylation]] degree of important mitochondrial enzymes, such as [[pyruvate dehydrogenase complex]] (PDC) and [[Oxoglutarate dehydrogenase complex|αあるふぁ-ketoglutarate dehydrogenase complex]] (αあるふぁ-KGDHC).<ref name=":0" /> Supplementation with lipoic acid does not restore mitochondrial function.<ref>{{Cite journal |last1=Hiltunen |first1=J. Kalervo |last2=Autio |first2=Kaija J. |last3=Schonauer |first3=Melissa S. |last4=Kursu |first4=V.A. Samuli |last5=Dieckmann |first5=Carol L. |last6=Kastaniotis |first6=Alexander J. |date=2010 |title=Mitochondrial fatty acid synthesis and respiration |url=https://linkinghub.elsevier.com/retrieve/pii/S000527281000112X |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |language=en |volume=1797 |issue=6–7 |pages=1195–1202 |doi=10.1016/j.bbabio.2010.03.006|pmid=20226757 }}</ref><ref name=":0" />

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 αあるふぁ-lipoic acids |journal= [[Journal of the American Chemical Society]] |volume= 79 |issue= 24 |pages= 6483–6487 |year= 1957 |doi= 10.1021/ja01581a033}}</ref><ref>{{cite journal |pmid= 14207116 |last1= Deguchi |first1= Y |last2= Miura |first2= K |title= Studies on the synthesis of thioctic acid and its related compounds. XIV. Synthesis of (+)-thioctamide |journal= Yakugaku Zasshi |volume= 84 |issue= 6 |date= June 1964 |pages= 562–3|doi= 10.1248/yakushi1947.84.6_562 |doi-access= free }}</ref> Advances in chiral chemistry led to more efficient technologies for manufacturing the single enantiomers by both [[classical resolution]] and [[asymmetric synthesis]] and the demand for RLA also grew at this time. In the 21st century, R/S-LA, RLA and SLA with high chemical and/or optical purities are available in industrial quantities. At the current time, most of the world supply of R/S-LA and RLA is manufactured in China and smaller amounts in Italy, Germany, and Japan. RLA is produced by modifications of a process first described by Georg Lang in a Ph.D. thesis and later patented by DeGussa.<ref>{{cite thesis |last= Lang |first= G |title= In Vitro Metabolism of a-Lipoic Acid Especially Taking Enantioselective Bio-transformation into Account |degree= Ph.D. |publisher= University of Münster |location= Münster, DE |year= 1992}}</ref><ref>{{cite patent |inventor1-last= Blaschke |inventor1-first= G |inventor2-last= Scheidmantel |inventor2-first= U |inventor3-last= Bethge |inventor3-first= H |inventor4= R Moeller, Beisswenger, T Huthmacher |title= Preparation and use of salts of the pure enantiomers of alpha-lipoic acid |country= US |number= 5281722 |status= patent |gdate= 1994-01-25 |assign1= DeGussa |fdate= 1992-11-12 |pridate= 1991-11-16 |postscript= .}}</ref> Although RLA is favored nutritionally due to its “vitamin"vitamin-like”like" role in metabolism, both RLA and R/S-LA are widely available as dietary supplements. Both [[stereospecific]] and non-stereospecific reactions are known to occur ''in vivo'' and contribute to the mechanisms of action, but evidence to date indicates RLA may be the [[eutomer]] (the nutritionally and therapeutically preferred form).<ref name=Carlson08/><ref>{{cite journal |pmid= 11684397 |last1= Packer |first1= L |last2= Kraemer |first2= K |last3= Rimbach |first3= G |title= Molecular aspects of lipoic acid in the prevention of diabetes complications |journal= Nutrition |volume= 17 |issue= 10 |date= October 2001 |pages= 888–95 |doi= 10.1016/S0899-9007(01)00658-X}}</ref>

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"/>

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.<ref>{{Cite journal |lastlast1=Prado |firstfirst1=Mario B. |last2=Adiao |first2=Karen Joy B. |date=2024-01-29 |title=Ranking Alpha Lipoic Acid and Gamma Linolenic Acid in Terms of Efficacy and Safety in the Management of Adults With Diabetic Peripheral Neuropathy: A Systematic Review and Network Meta-analysis |url=https://pubmed.ncbi.nlm.nih.gov/38295879 |journal=Canadian Journal of Diabetes |volume=48 |issue=4 |pages=S1499–2671(24)00023–6 |doi=10.1016/j.jcjd.2024.01.007 |issn=2352-3840 |pmid=38295879}}</ref> As of 2012, there was no good evidence alpha lipoic acid helps people with [[mitochondrial disorders]].<ref name="pmid22513923">{{cite journal | vauthors = Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF | title = Treatment for mitochondrial disorders | journal = Cochrane Database Syst Rev | issue = 4 | pages = CD004426 | date = April 2012 | volume = 2012 | pmid = 22513923 | doi = 10.1002/14651858.CD004426.pub3 | pmc = 7201312 }}</ref> A 2018 review recommended ALA as an anti-obesity supplement with low dosage (< 600&nbsp;mg/day) for a short period (<10 weeks); however, it is too expensive to be practical as a complementary therapy for obesity.<ref name="Namazi">{{cite journal | last1=Namazi | first1=Nazli | last2=Larijani | first2=Bagher | last3=Azadbakht | first3=Leila | title=Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta-analysis of clinical trials | journal=Clinical Nutrition| volume=37 | issue=2 | year=2018 | issn=0261-5614 | doi=10.1016/j.clnu.2017.06.002 | pages=419–428|pmid=28629898}}</ref>

* [[βべーた-lipoic acid]] is a thiosulfinate of αあるふぁ-lipoic acid

* [[Aminolevulinic acid]]

* {{Commons category-inline}}