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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Walker, Matthew T. Smith, Christopher J. Li, Ming Smith, Thomas J. |
| Description | Author Affiliation: Li M ( Donald Danforth Plant Science Center, St. Louis, Missouri 63132, USA.) |
| Abstract | Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 34 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-08-21 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Enzyme Inhibitors Chemistry Pharmacology Glutamate Dehydrogenase Antagonists & Inhibitors Indoles Phenols Allosteric Regulation Drug Effects Animals Bithionol Escherichia Coli Proteins Metabolism Guanosine Triphosphate Hexachlorophene Kinetics NADP Protein Conformation Protein Structure, Quaternary Protein Structure, Secondary Protein Structure, Tertiary Tetrahymena Enzymology Research Support, N.I.H., Extramural Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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