View source for Oxoglutarate dehydrogenase complex

{{Short description|Enzyme complex involved in Kreb's cycle}}
{{infobox enzyme
| Name       = oxoglutarate dehydrogenase
| EC_number  = 1.2.4.2
| CAS_number = 9031-02-1
| GO_code    = 0004591
| image      =
| width      =
| caption    =
}}
The '''oxoglutarate dehydrogenase complex''' ('''OGDC''') or '''α-ketoglutarate dehydrogenase complex''' is an enzyme complex, most commonly known for its role in the [[citric acid cycle]].

==Units==
Much like [[pyruvate dehydrogenase complex]] (PDC), this enzyme forms a complex composed of three components:

{| class="wikitable"
 ! Unit !! EC number !! Name !! Gene !! [[Cofactor (biochemistry)|Cofactor]]
 |-
 | E<sub>1</sub> || {{EC number|1.2.4.2}} || oxoglutarate dehydrogenase   || ''[[OGDH]]'' || [[thiamine pyrophosphate]] (TPP)
 |-
 | E<sub>2</sub> || {{EC number|2.3.1.61}} || dihydrolipoyl succinyltransferase || ''[[DLST]]'' || [[lipoic acid]], [[Coenzyme A]]
 |-
 | E<sub>3</sub> || {{EC number|1.8.1.4}} || dihydrolipoyl dehydrogenase || ''[[Dihydrolipoamide dehydrogenase|DLD]]'' || [[flavin adenine dinucleotide|FAD]], [[Nicotinamide adenine dinucleotide|NAD]]
|}
[[File:OGDH E1 TPP mechanism.PNG|thumb|450px|The OGDH E1-TPP mechanism involves the formation of a stabilized carbanion intermediate.]]

Three classes of these multienzyme complexes have been characterized: one specific for [[pyruvate]], a second specific for [[2-oxoglutarate]], and a third specific for [[branched-chain amino acid|branched-chain α-keto acid]]s. The oxoglutarate dehydrogenase complex has the same subunit structure and thus uses the same cofactors as the [[pyruvate dehydrogenase complex]] and the [[branched-chain alpha-keto acid dehydrogenase complex]] (TPP, CoA, lipoate, FAD and NAD). Only the E3 subunit is shared in common between the three enzymes.<ref>{{cite journal | vauthors = McCartney RG, Rice JE, Sanderson SJ, Bunik V, Lindsay H, Lindsay JG | title = Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alpha-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components | journal = The Journal of Biological Chemistry | volume = 273 | issue = 37 | pages = 24158–64 | date = September 1998 | pmid = 9727038 | doi = 10.1074/jbc.273.37.24158 | doi-access = free }}</ref>

==Properties==

===Metabolic pathways===
This enzyme participates in three different pathways:
* [[Citric acid cycle]] (KEGG link: [https://www.genome.jp/kegg/pathway/map/map00020.html MAP00020])
* [[Lysine]] degradation (KEGG link: [http://www.genome.jp/kegg/pathway/map/map00310.html MAP00310])
* [[Tryptophan]] metabolism (KEGG link: [http://www.genome.jp/kegg/pathway/map/map00380.html MAP00380])

===Kinetic properties===
The following values are from ''[[Azotobacter vinelandii]]''&nbsp;<sup>(1)</sup>:
* [[Michaelis-Menten kinetics|K<sub>M</sub>]]: 0.14 ± 0.04 mM
* V<sub>max</sub> : 9 ± 3 μmol.min<sup>−1</sup>.mg<sup>−1</sup>

==Citric acid cycle==

===Reaction===
The reaction catalyzed by this enzyme in the citric acid cycle is:
:[[α-ketoglutarate]] + [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] + [[Coenzyme A|CoA]] → [[Succinyl CoA]] + [[Carbon dioxide|CO<sub>2</sub>]] + [[NADH]]

[[Image:Oxoglutarate dehydrogenase (α-Ketoglutarate dehydrogenase).png|thumb|500px|center|Oxoglutarate dehydrogenase (α-Ketoglutarate dehydrogenase)]]

This reaction proceeds in three steps:
* [[decarboxylation]] of α-ketoglutarate,
* [[redox|reduction]] of NAD<sup>+</sup> to NADH,
* and subsequent transfer to [[Coenzyme A|CoA]], which forms the end product, [[succinyl CoA]].

[[Gibbs free energy|ΔG°']] for this reaction is -7.2 kcal mol<sup>−1</sup>. The energy needed for this oxidation is conserved in the formation of a thioester bond of [[succinyl CoA]].

===Regulation===
Oxoglutarate dehydrogenase is a key control point in the citric acid cycle. It is inhibited by its products, [[succinyl CoA]] and [[NADH]]. A high energy charge in the cell will also be inhibitive. ADP and calcium ions are allosteric activators of the enzyme.

By controlling the amount of available reducing equivalents generated by the [[Krebs cycle]], Oxoglutarate dehydrogenase has a downstream regulatory effect on [[oxidative phosphorylation]] and [[Adenosine triphosphate|ATP]] production.<ref name="TRETTER">{{cite journal | vauthors = Tretter L, Adam-Vizi V | title = Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 360 | issue = 1464 | pages = 2335–45 | date = December 2005 | pmid = 16321804 | pmc = 1569585 | doi = 10.1098/rstb.2005.1764 }}</ref> Reducing equivalents (such as NAD+/NADH) supply the electrons that run through the [[electron transport chain]] of oxidative phosphorylation. Increased Oxoglutarate dehydrogenase activation levels serve to increase the concentrations of NADH relative to NAD+. High NADH concentrations stimulate an increase in flux through oxidative phosphorylation.

While an increase in flux through this pathway generates ATP for the cell, the pathway also generates [[free radical]] species as a side product, which can cause oxidative stress to the cells if left to accumulate.

Oxoglutarate dehydrogenase is considered to be a redox sensor in the [[mitochondria]], and has an ability to change the functioning level of mitochondria to help prevent oxidative damage.<ref name="McLain">{{cite journal | vauthors = McLain AL, Szweda PA, Szweda LI | title = α-Ketoglutarate dehydrogenase: a mitochondrial redox sensor | journal = Free Radical Research | volume = 45 | issue = 1 | pages = 29–36 | date = January 2011 | pmid = 21110783 | pmc = 3169906 | doi = 10.3109/10715762.2010.534163 }}</ref> In the presence of a high concentration of free radical species, Oxoglutarate dehydrogenase undergoes fully reversible free radical mediated inhibition.<ref name="MCLAIN" /> In extreme cases, the enzyme can also undergo complete oxidative inhibition.<ref name="MCLAIN" />

When mitochondria are treated with excess [[hydrogen peroxide]], flux through the electron transport chain is reduced, and NADH production is halted.<ref name="MCLAIN">{{cite journal | vauthors = McLain AL, Cormier PJ, Kinter M, Szweda LI | title = Glutathionylation of α-ketoglutarate dehydrogenase: the chemical nature and relative susceptibility of the cofactor lipoic acid to modification | journal = Free Radical Biology & Medicine | volume = 61 | pages = 161–9 | date = August 2013 | pmid = 23567190 | pmc = 3883985 | doi = 10.1016/j.freeradbiomed.2013.03.020 }}</ref><ref name="APPLE">{{cite journal | vauthors = Applegate MA, Humphries KM, Szweda LI | title = Reversible inhibition of alpha-ketoglutarate dehydrogenase by hydrogen peroxide: glutathionylation and protection of lipoic acid | journal = Biochemistry | volume = 47 | issue = 1 | pages = 473–8 | date = January 2008 | pmid = 18081316 | doi = 10.1021/bi7017464 }}</ref> Upon consumption and removal of the free radical source, normal mitochondrial function is restored.

It is believed that the temporary inhibition of mitochondrial function stems from the reversible glutathionylation of the E2-lipoac acid domain of Oxoglutarate dehydrogenase.<ref name="APPLE" /> Glutathionylation, a form of [[post-translational modification]], occurs during times of increased concentrations of free radicals, and can be undone after hydrogen peroxide consumption via [[glutaredoxin]].<ref name="MCLAIN" /> Glutathionylation "protects" the lipoic acid of the E2 domain from undergoing oxidative damage, which helps spare the Oxoglutarate dehydrogenase complex from oxidative stress.

Oxoglutarate dehydrogenase activity is turned off in the presence of free radicals in order to protect the enzyme from damage. Once free radicals are consumed by the cell, the enzyme's activity is turned back on via glutaredoxin. The reduction in activity of the enzyme under times of oxidative stress also serves to slow the flux through the electron transport chain, which slows production of free radicals.

In addition to free radicals and the mitochondrial redox state, Oxoglutarate dehydrogenase activity is also regulated by ATP/ADP ratios, the ratio of Succinyl-CoA to CoA-SH, and the concentrations of various metal ion cofactors (Mg2+, Ca2+).<ref name="QI">{{cite journal | vauthors = Qi F, Pradhan RK, Dash RK, Beard DA | title = Detailed kinetics and regulation of mammalian 2-oxoglutarate dehydrogenase | journal = BMC Biochemistry | volume = 12 | issue = 1 | pages = 53 | date = September 2011 | pmid = 21943256 | pmc = 3195097 | doi = 10.1186/1471-2091-12-53 | doi-access = free }}</ref> Many of these [[allosteric]] regulators act at the E1 domain of the enzyme complex, but all three domains of the enzyme complex can be allosterically controlled.<ref name="STRUM">{{cite journal | vauthors = Strumilo S | year = 2005 | title = Often ignored facts about the control of the 2-oxoglutarate dehydrogenase complex | journal = Biochemistry and Molecular Biology Education | volume = 33 | issue = 4| pages = 284–287 | doi = 10.1002/bmb.2005.49403304284 | s2cid = 86257831 }}</ref> The activity of the enzyme complex is upregulated with high levels of ADP and Pi, Ca2+, and CoA-SH. The enzyme is inhibited by high ATP levels, high NADH levels, and high Succinyl-CoA concentrations.<ref name="STRUM" />

===Stress response===
Oxoglutarate dehydrogenase plays a role in the cellular response to stress. The enzyme complex undergoes a stress-mediated temporary inhibition upon acute exposure to stress. The temporary inhibition period sparks a stronger up-regulation response, allowing an increased level of oxoglutarate dehydrogenase activity to compensate for the acute stress exposure.<ref name="GRAF">{{cite journal | vauthors = Graf A, Trofimova L, Loshinskaja A, Mkrtchyan G, Strokina A, Lovat M, Tylicky A, Strumilo S, Bettendorff L, Bunik VI | display-authors = 6 | title = Up-regulation of 2-oxoglutarate dehydrogenase as a stress response | journal = The International Journal of Biochemistry & Cell Biology | volume = 45 | issue = 1 | pages = 175–89 | date = January 2013 | pmid = 22814169 | doi = 10.1016/j.biocel.2012.07.002 }}</ref> Acute exposures to stress are usually at lower, tolerable levels for the cell.

Pathophysiologies can arise when the stress becomes cumulative or develops into chronic stress. The up-regulation response that occurs after acute exposure can become exhausted if the inhibition of the enzyme complex becomes too strong.<ref name="GRAF" /> Stress in cells can cause a deregulation in the biosynthesis of the [[neurotransmitter]] [[glutamate]]. Glutamate toxicity in the brain is caused by a buildup of glutamate under times of stress. If oxoglutarate dehydrogenase activity is dysfunctional (no adaptive stress compensation), the build-up of glutamate cannot be fixed, and brain pathologies can ensue. Dysfunctional oxoglutarate dehydrogenase may also predispose the cell to damage from other toxins that can cause [[neurodegeneration]].<ref name="GIBSON">{{cite journal | vauthors = Gibson GE, Blass JP, Beal MF, Bunik V | title = The alpha-ketoglutarate-dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration | journal = Molecular Neurobiology | volume = 31 | issue = 1–3 | pages = 43–63 | year = 2005 | pmid = 15953811 | doi = 10.1385/mn:31:1-3:043 | s2cid = 10787919 }}</ref>

==Pathology==
2-Oxo-glutarate dehydrogenase is an [[autoantigen]] recognized in [[primary biliary cirrhosis]], a form of acute liver failure. These [[antibodies]] appear to recognize oxidized [[protein]] that has resulted from inflammatory immune responses. Some of these inflammatory responses are explained by [[gluten sensitivity]].<ref name="pmid17657817">{{cite journal | vauthors = Leung PS, Rossaro L, Davis PA, Park O, Tanaka A, Kikuchi K, Miyakawa H, Norman GL, Lee W, Gershwin ME | display-authors = 6 | title = Antimitochondrial antibodies in acute liver failure: implications for primary biliary cirrhosis | journal = Hepatology | volume = 46 | issue = 5 | pages = 1436–42 | date = November 2007 | pmid = 17657817 | pmc = 3731127 | doi = 10.1002/hep.21828 }}</ref> Other mitochondrial autoantigens include [[pyruvate dehydrogenase]] and [[branched-chain alpha-keto acid dehydrogenase complex]], which are antigens recognized by [[anti-mitochondrial antibodies]].

Activity of the 2-oxoglutarate dehydrogenase complex is decreased in many neurodegenerative diseases. [[Alzheimer's disease]], [[Parkinson's disease]], [[Huntington disease]], and [[supranuclear palsy]] are all associated with an increased oxidative stress level in the brain.<ref>{{cite journal | vauthors = Shi Q, Xu H, Yu H, Zhang N, Ye Y, Estevez AG, Deng H, Gibson GE | display-authors = 6 | title = Inactivation and reactivation of the mitochondrial α-ketoglutarate dehydrogenase complex | journal = The Journal of Biological Chemistry | volume = 286 | issue = 20 | pages = 17640–8 | date = May 2011 | pmid = 21454586 | pmc = 3093839 | doi = 10.1074/jbc.M110.203018 | doi-access = free }}</ref> Specifically for Alzheimer Disease patients, the activity of oxoglutarate dehydrogenase is significantly diminished.<ref name="SORBI">{{cite journal | vauthors = Sorbi S, Bird ED, Blass JP | title = Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain | journal = Annals of Neurology | volume = 13 | issue = 1 | pages = 72–8 | date = January 1983 | pmid = 6219611 | doi = 10.1002/ana.410130116 | s2cid = 29106528 }}</ref> This leads to a possibility that the portion of the TCA cycle responsible for causing the build-up of free radical species in the brain of patients is a malfunctioning oxoglutarate dehydrogenase complex. The mechanism for disease-related inhibition of this enzyme complex remains relatively unknown.

In the metabolic disease [[combined malonic and methylmalonic aciduria]] (CMAMMA) due to [[ACSF3]] deficiency, [[mitochondrial fatty acid synthesis]] (mtFAS) is impaired, which is the precursor reaction of [[lipoic acid]] biosynthesis.<ref>{{Cite journal |last=Levtova |first=Alina |last2=Waters |first2=Paula J. |last3=Buhas |first3=Daniela |last4=Lévesque |first4=Sébastien |last5=Auray‐Blais |first5=Christiane |author-link5=Christiane Auray |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|url-access=subscription }}</ref><ref name=":0">{{Cite journal |last=Wehbe |first=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 |title=The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism |url=https://linkinghub.elsevier.com/retrieve/pii/S1388198119301349 |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |language=en |volume=1864 |issue=11 |pages=1629–1643 |doi=10.1016/j.bbalip.2019.07.012|url-access=subscription }}</ref> The result is a reduced [[Post-translational modification#PTMs involving addition of functional groups|lipoylation]] degree of important mitochondrial enzymes, such as oxoglutarate dehydrogenase complex (OGDC).<ref name=":0" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Bunik V, Westphal AH, de Kok A | title = Kinetic properties of the 2-oxoglutarate dehydrogenase complex from Azotobacter vinelandii evidence for the formation of a precatalytic complex with 2-oxoglutarate | journal = European Journal of Biochemistry | volume = 267 | issue = 12 | pages = 3583–91 | date = June 2000 | pmid = 10848975 | doi = 10.1046/j.1432-1327.2000.01387.x | doi-access = free }}
* {{cite journal | vauthors = Bunik VI, Strumilo S | year = 2009 | title = Regulation of Catalysis Within Cellular Network: Metabolic and Signaling Implications of the 2-Oxoglutarate Oxidative Decarboxylation | journal = Current Chemical Biology | volume = 3 | issue = 3| pages = 279–290 | doi=10.2174/187231309789054904}}
* {{cite journal | vauthors = Bunik VI, Fernie AR | title = Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation | journal = The Biochemical Journal | volume = 422 | issue = 3 | pages = 405–21 | date = August 2009 | pmid = 19698086 | doi = 10.1042/bj20090722 }}
* {{cite journal | vauthors = Trofimova L, Lovat M, Groznaya A, Efimova E, Dunaeva T, Maslova M, Graf A, Bunik V | display-authors = 6 | title = Behavioral impact of the regulation of the brain 2-oxoglutarate dehydrogenase complex by synthetic phosphonate analog of 2-oxoglutarate: implications into the role of the complex in neurodegenerative diseases | journal = International Journal of Alzheimer's Disease | volume = 2010 | pages = 749061 | date = October 2010 | pmid = 21049004 | pmc = 2964918 | doi = 10.4061/2010/749061 | doi-access = free }}
{{refend}}

== External links ==
* {{MeshName|Oxoglutarate+dehydrogenase}}

{{Multienzyme complexes}}
{{Citric acid cycle enzymes}}
{{Mitochondrial enzymes}}
{{Autoantigens}}
{{Aldehyde/Oxo oxidoreductases}}
{{Enzymes}}
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[[Category:EC 1.2.4]]
[[Category:Autoantigens]]
[[Category:Citric acid cycle]]