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      Alpha-Ketoglutarate: Physiological Functions and Applications

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          Abstract

          Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications.

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          Glutamate uptake.

          N C Danbolt (2001)
          Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.
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            Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

            Pankaj Kapahi, Brian M. Zid, Tony Harper … (2004)
            In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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              Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria.

              J. P. Abrahams, A Leslie, R. Lutter … (1994)
              In the crystal structure of bovine mitochondrial F1-ATPase determined at 2.8 A resolution, the three catalytic beta-subunits differ in conformation and in the bound nucleotide. The structure supports a catalytic mechanism in intact ATP synthase in which the three catalytic subunits are in different states of the catalytic cycle at any instant. Interconversion of the states may be achieved by rotation of the alpha 3 beta 3 subassembly relative to an alpha-helical domain of the gamma-subunit.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomol Ther (Seoul)
                Journal ID (iso-abbrev): Biomol Ther (Seoul)
                Journal ID (publisher-id): Biomol Ther (Seoul)
                Journal ID (publisher-id): ksp
                Title: Biomolecules & Therapeutics
                Publisher: The Korean Society of Applied Pharmacology
                ISSN (Print): 1976-9148
                ISSN (Electronic): 2005-4483
                Publication date (Print): January 2016
                Publication date (Electronic): 01 January 2016
                Volume: 24
                Issue: 1
                Pages: 1-8
                Affiliations
                Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P.R. China
                Author notes
                [* ]Corresponding Author: E-mail: diyanli@ 123456sicau.edu.cn , Tel: +86-028-8629-0111, Fax: +86-028-8629-0111
                Article
                Publisher ID: bt-24-001
                DOI: 10.4062/biomolther.2015.078
                PMC ID: 4703346
                PubMed ID: 26759695
                SO-VID: 0471e8be-7ce2-4ff3-b490-8629e205d389
                Copyright © Copyright © 2016, The Korean Society of Applied Pharmacology
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 11 June 2015
                Date revision received : 21 August 2015
                Date accepted : 28 August 2015
                Categories
                Subject: Review

                Keywords: alpha-ketoglutarate,functions,lifespan extension,applications
                Data availability:
                Keywords: alpha-ketoglutarate, functions, lifespan extension, applications

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