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Glutamate Dehydrogenase: Structure, Allosteric Regulation, and Role in Insulin Homeostasis

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Abstract

Glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate. Only in the animal kingdom is this enzyme heavily allosterically regulated by a wide array of metabolites. The major activators are ADP and leucine and inhibitors include GTP, palmitoyl CoA, and ATP. Spontaneous mutations in the GTP inhibitory site that lead to the hyperinsulinism/hyperammonemia (HHS) syndrome have shed light as to why mammalian GDH is so tightly regulated. Patients with HHS exhibit hypersecretion of insulin upon consumption of protein and concomitantly extremely high levels of ammonium in the serum. The atomic structures of four new inhibitors complexed with GDH complexes have identified three different allosteric binding sites. Using a transgenic mouse model expressing the human HHS form of GDH, at least three of these compounds blocked the dysregulated form of GDH in pancreatic tissue. EGCG from green tea prevented the hyper-response to amino acids in whole animals and improved basal serum glucose levels. The atomic structure of the ECG–GDH complex and mutagenesis studies is directing structure-based drug design using these polyphenols as a base scaffold. In addition, all of these allosteric inhibitors are elucidating the atomic mechanisms of allostery in this complex enzyme.

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Acknowledgments

This work was supported by National Institutes of Health (NIH) Grant DK072171 (to T.J.S.), NIH Grant DK53012 and American Diabetes Association Research Award 1-05-RA-128 (to C.A.S.), and NIH Grant DK19525 for islet biology and radioimmunoassay cores. A special thanks goes to Blue California (www.bluecal-ingredients.com) for the generous gift of EGCG used for the whole animal studies.

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Authors and Affiliations

  1. Donald Danforth Plant Science Center, 975 North Warson Road, Saint Louis, MO, 63132, USA

    Ming Li, Aron Allen & Thomas J. Smith

  2. Division of Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Changhong Li & Charles A. Stanley

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  1. Ming Li
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  2. Changhong Li
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  3. Aron Allen
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Correspondence to Thomas J. Smith.

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Li, M., Li, C., Allen, A. et al. Glutamate Dehydrogenase: Structure, Allosteric Regulation, and Role in Insulin Homeostasis. Neurochem Res 39, 433–445 (2014). https://doi.org/10.1007/s11064-013-1173-2

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