Structural basis for the activity and regulation of human α-ketoglutarate dehydrogenase revealed by Cryo-EM
Abstract
The human mitochondrial alpha-ketoglutarate (α-KG) dehydrogenase complex (hKGDHc) is a well-studied macromolecular enzyme that converts α-KG to succinyl-CoA and NADH. Abnormalities of the complex lead to several diseases, including neurodegenerative disorders. Despite its importance in human metabolism and diseases, structural information on hKGDHc is not well defined. Here, we report the 2.92 Å resolution cryo-electron microscopy (EM) structure of its E1 component 2-oxoglutarate dehydrogenase (OGDH). The density map comprised residues 129-1,023, which is nearly the full length of OGDH. The structure clearly shows the active site and Ca 2+ binding site of OGDH. This structural information will improve our understanding of the structure and function of hKGDHc and benefit pharmaceutical and basic science targeting this enzyme complex.
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The pathway of glutamate into the TCA cycle mainly occurs in neurons.
“This pathway mainly occurs in neurons (Dobolyi et al., 2020; Zhong et al., 2022), and OGDHC is a limiting step in this process (Mkrtchyan et al., 2018).”
From Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures (2026) · cites this paper as Zhong et al., 2022
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Vaglio-Garro, A., Theuermann, M., Sweis, K. E., Zavadskis, S., Kokas, M., Környei, Z., Karas, M., Tretter, L., Komlódi, T., Weidinger, A., et al. (2026) · eneuro · doi:10.1523/eneuro.0439-25.2026
- Authors
- Zhong, Y., Gao, Y., Zhou, D., Ma, X., Chen, H., Xu, Y., Yang, W., & Yu, X.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Southern University of Science and Technology (CN)
- Fudan University (CN)
- Corresponding author
- Yang, Wen
- Yu, Xiang
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2022-04
- Volume
- 602
- Pages
- 120-126
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W4214884593
- Cited by
- 30
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 5
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- alpha-ketoglutarate dehydrogenase complex, 2-oxoglutarate dehydrogenase, mitochondrial enzymes, enzyme structure, active site, calcium binding sites, succinyl-CoA, NADH, neurodegenerative diseases, enzyme regulation
- MeSH terms
- Binding Sites, Humans, Ketoglutarate Dehydrogenase Complex, Ketoglutaric Acids, Mitochondria, Cryoelectron Microscopy
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