Ogdh Protein is involved in cellular processes relevant to neurodegeneration. For detailed information, refer to the References section.
OGDH encodes the E1 subunit of alpha-ketoglutarate dehydrogenase complex (α-KGDH), a key enzyme in the TCA cycle that converts α-ketoglutarate to succinyl-CoA with the production of NADH. [1]
| Protein Name | Alpha-Ketoglutarate Dehydrogenase |
|---|---|
| Gene | [OGDH](/genes/ogdh) |
| UniProt ID | [Q02218](https://www.uniprot.org/uniprot/Q02218) |
| PDB Structure IDs | 1T0L, 3DSS |
| Molecular Weight | 116 kDa (E1 subunit) |
| Subcellular Localization | Mitochondria (matrix) |
| Protein Family | Alpha-ketoacid dehydrogenase family |
α-KGDH is a multienzyme complex consisting of three subunits: OGDH (E1α), DLST (E2), and DLD (E3). The E1 subunit is a homodimer that requires thiamine pyrophosphate (TPP) as a cofactor.
Alpha-ketoglutarate dehydrogenase (α-KGDH) catalyzes the second NADH-producing step in the TCA cycle:
α-ketoglutarate + CoA + NAD+ → succinyl-CoA + NADH + CO2
α-KGDH is a rate-limiting enzyme of the TCA cycle and is highly sensitive to oxidative stress. It produces NADH for oxidative phosphorylation and succinyl-CoA for the TCA cycle.
The enzyme requires thiamine pyrophosphate (TPP) as a cofactor. It is regulated by substrate availability, product inhibition, and phosphorylation.
In neurons, α-KGDH is crucial for energy production and also provides succinyl-CoA for neurotransmitter synthesis (GABA and glutamate).
Alzheimer Disease: α-KGDH activity is dramatically reduced in AD brains (by 50-70%). This is one of the earliest and most consistent metabolic defects in AD, preceding clinical symptoms.
Parkinson Disease: α-KGDH activity is reduced in PD brains and in models of PD. The enzyme is particularly sensitive to oxidative stress, which is elevated in PD.
Aging: α-KGDH activity declines with age, contributing to reduced mitochondrial function and cognitive decline.
Cancer: α-KGDH is downregulated in many cancers, limiting carbon flow through the TCA cycle.
There are no direct α-KGDH-targeted drugs in clinical use. Research directions include: