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AKGDH


Official Full Name
AKGDH
Background
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.
Synonyms
2-ketoglutarate dehydrogenase; 2-oxoglutarate dehydrogenase; 2-oxoglutarate:lipoate oxidoreductase; 2-oxoglutarate:lipoamide 2-oxidoreductase (decarboxylating and acceptor-succinylating); α-ketoglutarate dehydrogenase; αketoglutaric acid dehydrogenase; α-ketoglutaric dehydrogenase; α-oxoglutarate dehydrogenase; AKGDH; OGDC; ketoglutaric dehydrogenase; oxoglutarate decarboxylase; oxoglutarate dehydrogenase; oxoglutarate dehydrogenase (lipoamide); EC 1.2.4.2; 9031-02-1

Catalog
Product Name
EC No.
CAS No.
Source
Price
CatalogEXWM-1218
EC No.EC 1.2.4.2
CAS No.9031-02-1
Source
CatalogNATE-0495
EC No.EC 1.2.4.2
CAS No.9031-02-1
SourcePorcine heart
Related Reading

α-ketoglutarate dehydrogenase (α-KGDH) is a Krebs cycle enzyme, which is responsible for converting α-ketoglutarate, coenzyme A and NAD+ into succinyl-CoA, NADH and CO2. This non-equilibrium reaction requires thiamine pyrophosphate as a cofactor. Many features of α-KGDH can distinguish it from other important enzymes in the bioenergy process. First, the enzyme is highly regulated and is the primary site of the metabolic flux through the Krebs cycle. The mammalian enzymes are inhibited by the end products succinyl-CoA and NADH. The regulation of α-KGDH is very complicated and is affected ATP/ADP ratio, NADH/NAD+ ratio, calcium and substrate availability in mitochondria. Therefore, it is also related to the activity of NAD+-isocitrate dehydrogenase. α-KGDH is a complex enzyme consisting of multiple copies of three subunits, namely: thiamine pyrophosphate-dependent dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and dihydrolipoamide dehydrogenase (E3). α-KGDH may be an important target of reactive oxygen species (ROS) in cells, and an important regulatory site for mitochondrial metabolism, and may play a key role in bioenergy deficiency. On the other hand, it has recently been discovered that the enzyme itself can produce ROS, which may help induce oxidative stress.   

Metabolic flux in the Krebs cycle during oxidative stress when aconitase is completely inactivated Figure 1. Metabolic flux in the Krebs cycle during oxidative stress when aconitase is completely inactivated (Tretter, L.; Adam-Vizi, V. 2005)

α-KGDH is a crucial target of ROS in the mitochondrial

The fragmentation products of the lipid peroxidation reaction contain highly toxic aldehydes, among which 4-hydroxy-2-nonenal (HNE) is the most reactive product. Exposure of cardiac mitochondria to HNE will cause a decrease in α-KGDH activity and inhibit the NADH-linked state three respiration. In addition to α-KGDH, HNE can also inhibit pyruvate dehydrogenase. HNE cannot change the complex of other mitochondrial dehydrogenases and complexes of the respiratory chain. When studying the effect of HNE on the isolated α-KGDH and PDH, it was found that the target of HNE was lipoic acid covalently bound to the E2 subunit of α-KGDH and PDH. Compared with other enzymes, α-KGDH appears to be more sensitive to disturb homeostatic factors. In post-mortem mouse brain samples, the activity of α-KGDH was rapidly lost, while the activity of another TPP-dependent enzyme PDH lasted at least 24 h. There is a correlation between the level of lactate in brain samples and the decrease in α-KGDH activity, which may indicate that α-KGDH is more sensitive to antemortem hypoxia than other enzymes involved in metabolism. The optimal pH range of mitochondrial α-KGDH is very narrow, between 7.2 and 7.4. When it falls below or exceeds this range, the enzyme activity significantly decreases. The α-KGDH purified from pig heart exhibits a broader pH optimum, and its pH value is between 6.6 and 7.4 when determining the maximum activity of the enzyme.    

Generation of reactive oxygen species by α-KGDH Figure 2. Generation of reactive oxygen species by α-KGDH (Tretter, L.; Adam-Vizi, V. 2005)

α-KGDH in neurodegeneration

Decreased α-KGDH activity is related to mitochondrial deficiency, which is crucial in the neurodegenerative process of certain neurodegenerative diseases. The characteristic change of bioenergetic parameters in the brains of Parkinson's disease patients is the decreased activity of respiratory chain complex I. Interestingly, the only other altered enzyme found in the post-mortem substantia nigra samples was α-KGDH. The inhibitory effect of MPP+ and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine) and other isoquinoline derivatives on this enzyme highlight the role of the enzyme in disease pathology. The α-KGDH activity in the brain of patients of Alzheimer's disease is reduced, including the regions affected by the disease and the normal regions. The α-KGDH in fibroblasts of patients with presenilin-1 mutation decreases or had increased vulnerability to oxidative stress. Recent studies have reported that in the temporal cortex of Alzheimer's disease, α-KGDH enriched neurons are reduced or even lost. Decreased enzyme activity may not be a causative event in the pathophysiology of Alzheimer's disease, but the mitochondrial dysfunction caused by inhibition of α-KGDH may be a key factor in the degeneration process. In the animal model of thiamine deficiency, the key role of reduced α-KGDH activity in events leading to cell death in the central nervous system is very clearly demonstrated, in which the activity of α-KGDH is reduced in the brain region where the neurons die, whereas in regions that survive, the activity of the enzyme was preserved. The exact role and pathological significance of α-KGDH in the neurodegenerative process are not yet clear, but given the key role of this enzyme in limiting the metabolism during oxidative stress and the production of ROS, it is very important to solve this problem.

Reference

  1. Tretter, L.; Adam-Vizi, V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci. 2005, 360(1464): 2335-2345.

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