Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use
Open accessAbstract
Alpha-ketoglutarate (AKG), an endogenous intermediary metabolite in the Krebs cycle, is a molecule involved in multiple metabolic and cellular pathways. It functions as an energy donor, a precursor in the amino acid biosynthesis, a signalling molecule, as well as a regulator of epigenetic processes and cellular signalling via protein binding. AKG is an obligatory co-substrate for 2-oxoglutarate-dependent dioxygenases, which catalyse hydroxylation reactions on various types of substrates. It regulates the activity of prolyl-4 hydroxylase, which controls the biosynthesis of collagen, a component of bone tissue. AKG also affects the functioning of prolyl hydroxylases, which, in turn, influences the function of the hypoxia-inducible factor, an important transcription factor in cancer development and progression. Additionally, it affects the functioning of enzymes that influence epigenetic modifications of chromatin: ten-eleven translocation hydroxylases involved in DNA demethylation and the Jumonji C domain containing lysine demethylases, which are the major histone demethylases. Thus, it regulates gene expression. The metabolic and extrametabolic function of AKG in cells and the organism open many different fields for therapeutic interventions for treatment of diseases. This review presents the results of studies conducted with the use of AKG in states of protein deficiency and oxidative stress conditions. It also discusses current knowledge about AKG as an immunomodulatory agent and a bone anabolic factor. Additionally, the regulatory role of AKG and its structural analogues in carcinogenesis as well as the results of studies of AKG as an anticancer agent are discussed.
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Recent studies have shown that AKG also functions as a signaling molecule and acts as a regulator of epigenetic processes and cellular signaling, via protein binding with many different AKG sensors.
“However, recent studies have shown that AKG also functions as a signaling molecule and acts as a regulator of epigenetic processes and cellular signaling, via protein binding with many different AKG sensors (Zdzisinska et al, 2017).”
From Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation (2020) · cites this paper as Zdzisinska et al, 2017
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References 212 · Cited by 221
- Authors
- Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M.
- Affiliations
- Maria Curie-Skłodowska University (PL)
- Corresponding author
- Zdzisińska, Barbara
- ORCID
- Zdzisińska, Barbara
- Venue
- Archivum Immunologiae et Therapiae Experimentalis
- Publisher
- Walter de Gruyter GmbH
- Published
- 2016-06-20
- Volume
- 65
- Issue
- 1
- Pages
- 21-36
- ISSN
- 0004-069X (ISSN-L)
- 1661-4917
- PMC
- PMC5274648
- OpenAlex
- W2463493657
- Cited by
- 221
- References
- 212
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 29 · 2023: 24 · 2022: 32 · 2021: 33 · 2020: 26 · 2019: 10 · 2018: 11 · 2017: 8 · 2016: 3
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Archivum Immunologiae et Therapiae Experimentalis (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Narodowe Centrum Nauki (2013/11/B/NZ4/04557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- alpha-ketoglutarate, TCA cycle, 2-oxoglutarate-dependent dioxygenase, prolyl hydroxylase, collagen synthesis, hypoxia-inducible factor, DNA demethylation, epigenetic regulation, protein deficiency, oxidative stress, immunomodulation, bone formation, carcinogenesis, anticancer agents, Krebs cycle intermediates
- MeSH terms
- Animals, Hypoxia, Antineoplastic Agents, Antioxidants, Citric Acid Cycle, Humans, Ketoglutaric Acids, Mutation, Signal Transduction, Oxidative Stress, DNA Methylation, Dietary Supplements, Epigenesis, Genetic, Anabolic Agents, Hypoxia-Inducible Factor 1, alpha Subunit
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