Editing Lipoic acid (section)

==Biological function==
Lipoic acid is a cofactor for five enzymes or classes of enzymes: [[pyruvate dehydrogenase]], [[Oxoglutarate dehydrogenase complex|α-ketoglutarate dehydrogenase]], the [[glycine cleavage system]], [[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain alpha-keto acid dehydrogenase]], and the α-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 dithiol) 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>

===Biosynthesis and attachment===
Most endogenously produced RLA are not "[[Free fatty acid|free]]" because octanoic acid, the [[Precursor (chemistry)|precursor]] to RLA, is bound to the enzyme complexes prior to enzymatic insertion of the sulfur atoms. As a cofactor, RLA is [[Covalent bond|covalently]] attached by an [[amide bond]] to a terminal [[lysine]] [[Residue (chemistry)#Biochemistry|residue]] of the enzyme's lipoyl [[Protein domain|domains]].
The precursor to lipoic acid, [[octanoic acid]], is made via [[Mitochondrial fatty acid synthesis|mitochondrial fatty acid biosynthesis]] in the form of octanoyl-[[acyl carrier protein]].<ref name=lpi/> The octanoate is transferred as a [[thioester]] of [[acyl carrier protein]] from mitochondrial fatty acid biosynthesis to an [[amide]] of the lipoyl domain protein by an [[enzyme]] called an [[Lipoyl(octanoyl) transferase|octanoyltransferase]].<ref name=lpi/> Two [[Hydrogen|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>

===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"
|+
!EC-number
!Enzyme
!Gene
!Multienzyme complex
!Role of the complex
|-
|[[Enzyme Commission number|EC]] [https://enzyme.expasy.org/EC/2.3.1.12 2.3.1.12]
|[[dihydrolipoyl transacetylase]] (E2)
|[[DLAT]]
|[[pyruvate dehydrogenase complex]] (PDC)
|Connection of [[glycolysis]] with the [[citric acid cycle]]
|-
| 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)
|[[Citric acid cycle]] enzyme
|-
|[[2-oxoadipate dehydrogenase complex]] (OADHC)
|[[Lysine]] degradation
|-
|EC [https://enzyme.expasy.org/EC/2.3.1.168 2.3.1.168]
|[[dihydrolipoyl transacylase]] (E2)
|[[DBT (gene)|DBT]]
|[[Branched-chain alpha-keto acid dehydrogenase complex|branched-chain α-ketoacid dehydrogenase complex]] (BCKDC)
|[[Leucine]], [[isoleucine]] and [[valine]] degradation
|-
|
|[[GCSH|H-protein]]
|[[GCSH]]
|[[glycine cleavage system]] (GCS)
|[[Glycine]] and [[serine]] metabolism, [[folate]] metabolism
|}
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&nbsp;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.{{cn|date=November 2024}}

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&nbsp;ng/mL following acid hydrolysis, which releases protein-bound lipoic acid. Enzymatic hydrolysis of protein bound lipoic acid released 1.4−11.6&nbsp;ng/mL and <1-38.2&nbsp;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 |chapter= High-performance liquid chromatography methods for determination of lipoic and dihydrolipoic acid in human plasma |title= Vitamins and Coenzymes Part I |volume= 279 |year= 1997 |pages= 159–66 |series= [[Methods in Enzymology]] |isbn= 9780121821807}}</ref><ref>{{cite journal |doi= 10.1016/0378-4347(95)00225-8 |pmid= 8581134 |last1= Teichert |first1= J |last2= Preiss |first2= R |title= Determination of lipoic acid in human plasma by high-performance liquid chromatography with electrochemical detection |journal= [[Journal of Chromatography B]] |volume= 672 |issue= 2 |date= October 1995 |pages=277–81}}</ref><ref>{{cite journal |pmid= 1490813 |last1= Teichert |first1= J |last2= Preiss |first2= R |title= HPLC-methods for determination of lipoic acid and its reduced form in human plasma |journal= International Journal of Clinical Pharmacology, Therapy, and Toxicology |volume= 30 |issue= 11 |date= November 1992 |pages= 511–2}}</ref>

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/>

Lipoic acid is metabolized in a variety of ways when given as a dietary supplement in mammals.<ref name=lpi/><ref name="ReferenceA">{{Cite journal  |last1= Schupke |first1= H |last2= Hempel |first2= R |last3= Peter |first3= G |last4= Hermann |first4= R |last5= Wessel |first5= K |last6= Engel |first6= J |last7= Kronbach |first7= T |display-authors= 4 |title= New metabolic pathways of alpha-lipoic acid |journal= [[Drug Metabolism and Disposition]] |volume= 29 |issue= 6 |pages= 855–62 |date= June 2001 |pmid= 11353754}}</ref> Degradation to tetranorlipoic acid, oxidation of one or both of the sulfur atoms to the sulfoxide, and S-methylation of the sulfide were observed. Conjugation of unmodified lipoic acid to glycine was detected especially in mice.<ref name="ReferenceA"/> Degradation of lipoic acid is similar in humans, although it is not clear if the sulfur atoms become significantly oxidized.<ref name=lpi/><ref>{{Cite journal |last1= Teichert |first1= J |last2= Hermann |first2= R |last3= Ruus |first3= P |last4= Preiss |first4= R |title= Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers |journal= [[The Journal of Clinical Pharmacology|Journal of Clinical Pharmacology]] |volume= 43 |issue= 11 |pages= 1257–67 |date= November 2003 |doi= 10.1177/0091270003258654 |pmid= 14551180|s2cid= 30589232 }}</ref> Apparently mammals are not capable of utilizing lipoic acid as a sulfur source.