The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is a mitochondrial multienzyme complex, most commonly known for its role in the citric acid cycle. It belongs to the 2-oxoacid dehydrogenase complex family.
Units
Much like pyruvate dehydrogenase complex (PDC), this enzyme forms a complex composed of three components:
{| class="wikitable"
! Unit!! EC number !! Name !! Gene !! Cofactor
|-
| E1o || || oxoglutarate dehydrogenase || OGDH || thiamine pyrophosphate (TPP)
|-
| E2o || || dihydrolipoyl succinyltransferase || DLST || lipoic acid, Coenzyme A
|-
| E3 || || dihydrolipoyl dehydrogenase || DLD || FAD, NAD
|}
thumb|450px|The OGDH E1-TPP mechanism involves the formation of a stabilized carbanion intermediate.
Four members of these multienzyme complexes have been characterized: one specific for pyruvate, a second specific for 2-oxoglutarate, a third specific for 2-oxoadipate, and a fourth specific for branched-chain α-keto acids. The oxoglutarate dehydrogenase complex has the same subunit structure and thus uses the same cofactors (TPP, CoA, lipoate, FAD and NAD) as:
- the pyruvate dehydrogenase complex (PDHC),
- the 2-oxoadipate dehydrogenase complex (OADHC),
- and the branched-chain alpha-keto acid dehydrogenase complex (BCKDC).
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 of lysine and tryptophan catabolism. 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. In the presence of a high concentration of free radical species, Oxoglutarate dehydrogenase undergoes fully reversible free radical mediated inhibition. 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. 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. 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. 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.
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. 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. Specifically for Alzheimer Disease patients, the activity of oxoglutarate dehydrogenase is significantly diminished. 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. The result is a reduced lipoylation degree of important mitochondrial enzymes, such as oxoglutarate dehydrogenase complex (OGDC).