| oxoglutarate dehydrogenase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.2.4.2 | ||||||||
| CAS no. | 9031-02-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
Theoxoglutarate dehydrogenase complex (OGDC) orα-ketoglutarate dehydrogenase complex is amitochondrialmultienzyme complex, most commonly known for its role in thecitric acid cycle. It belongs to the2-oxoacid dehydrogenase complex family.
Much likepyruvate dehydrogenase complex (PDC), this enzyme forms a complex composed of three components:
| Unit[1] | EC number | Name | Gene | Cofactor |
|---|---|---|---|---|
| E1o | EC1.2.4.2 | oxoglutarate dehydrogenase | OGDH | thiamine pyrophosphate (TPP) |
| E2o | EC2.3.1.61 | dihydrolipoyl succinyltransferase | DLST | lipoic acid,Coenzyme A |
| E3 | EC1.8.1.4 | dihydrolipoyl dehydrogenase | DLD | FAD,NAD |
Four members of these multienzyme complexes have been characterized: one specific forpyruvate, a second specific for2-oxoglutarate, a third specific for2-oxoadipate, and a fourth specific forbranched-chain α-keto acids.[2] The oxoglutarate dehydrogenase complex has the same subunit structure and thus uses the same cofactors (TPP, CoA, lipoate, FAD and NAD) as:
Among these, OGDC and OADHC are particularly closely related, as they not only share the same E2 and E3 components, but also catalyze chemically similar reactions within adjacent steps oflysine andtryptophan catabolism.[3][1] Notably, all four complexes rely on a common E3 subunit that is also employed by theglycine cleavage system (GCS) in the form of its L-protein, despite the GCS not belonging to this enzyme family.
This enzyme participates in three different pathways:
The following values are fromAzotobacter vinelandii (1):
The reaction catalyzed by this enzyme in the citric acid cycle is:
.png)
This reaction proceeds in three steps:
ΔG°' for this reaction is -7.2 kcal mol−1. The energy needed for this oxidation is conserved in the formation of a thioester bond ofsuccinyl CoA.
Oxoglutarate dehydrogenase is a key control point in the citric acid cycle. It is inhibited by its products,succinyl CoA andNADH. 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 theKrebs cycle, Oxoglutarate dehydrogenase has a downstream regulatory effect onoxidative phosphorylation andATP production.[4] Reducing equivalents (such as NAD+/NADH) supply the electrons that run through theelectron 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 generatesfree radical species as a side product, which can causeoxidative stress to the cells if left to accumulate.
Oxoglutarate dehydrogenase is considered to be a redox sensor in themitochondria, and has an ability to change the functioning level of mitochondria to help prevent oxidative damage.[5] In the presence of a high concentration of free radical species, Oxoglutarate dehydrogenase undergoes fully reversible free radical mediated inhibition.[6] In extreme cases, the enzyme can also undergo complete oxidative inhibition.[6]
When mitochondria are treated with excesshydrogen peroxide, flux through the electron transport chain is reduced, and NADH production is halted.[6][7] 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.[7] Glutathionylation, a form ofpost-translational modification, occurs during times of increased concentrations of free radicals, and can be undone after hydrogen peroxide consumption viaglutaredoxin.[6] 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+).[8] Many of theseallosteric regulators act at the E1 domain of the enzyme complex, but all three domains of the enzyme complex can be allosterically controlled.[9] 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.[9]
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.[10] 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.[10] Stress in cells can cause a deregulation in the biosynthesis of theneurotransmitterglutamate. 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 causeneurodegeneration.[11]
2-Oxo-glutarate dehydrogenase is anautoantigen recognized inprimary biliary cirrhosis, a form of acute liver failure. Theseantibodies appear to recognize oxidizedprotein that has resulted from inflammatory immune responses. Some of these inflammatory responses are explained bygluten sensitivity.[12] Other mitochondrial autoantigens includepyruvate dehydrogenase andbranched-chain alpha-keto acid dehydrogenase complex, which are antigens recognized byanti-mitochondrial antibodies.
Activity of the 2-oxoglutarate dehydrogenase complex is decreased in many neurodegenerative diseases.Alzheimer's disease,Parkinson's disease,Huntington disease, andsupranuclear palsy are all associated with an increased oxidative stress level in the brain.[13] Specifically for Alzheimer Disease patients, the activity of oxoglutarate dehydrogenase is significantly diminished.[14] 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 diseasecombined malonic and methylmalonic aciduria (CMAMMA) due toACSF3 deficiency,mitochondrial fatty acid synthesis (mtFAS) is impaired, which is the precursor reaction oflipoic acid biosynthesis.[15][16] The result is a reducedlipoylation degree of important mitochondrial enzymes, such as oxoglutarate dehydrogenase complex (OGDC).[16]
