HgEDTA Complex Inhibits GTP Interactions with the E-Site of Brain β-Tubulin
| Autor: | B E Haley, J C Pendergrass, J T Slevin, E F Duhr |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Azides GTP' Photochemistry Affinity label macromolecular substances In Vitro Techniques Toxicology Microtubule polymerization Rats Sprague-Dawley chemistry.chemical_compound Tubulin Microtubule Animals Humans Magnesium Chelation Cytoskeleton Edetic Acid Pharmacology Binding Sites biology Brain Affinity Labels Mercury Rats EGTA chemistry Biochemistry biology.protein Guanosine Triphosphate Phosphorus Radioisotopes Protein Binding |
| Zdroj: | Toxicology and Applied Pharmacology. 122:273-280 |
| ISSN: | 0041-008X |
| Popis: | We have found that EDTA and EGTA complexes of Hg2+, which conventional wisdom has assumed are biologically inert, are potentially injurious to the neuronal cytoskeleton. Tubulin, a major protein component of the neuronal cytoskeleton, is the target of multiple toxicants, including many heavy metal ions. Among the mercurials, inorganic mercuric ion (Hg2+) is one of the most potent inhibitors of microtubule polymerization both in vivo and in vitro. In contrast to other heavy metals, the capacity of Hg2+ to inhibit microtubule polymerization or disrupt formed microtubules cannot be prevented by the addition of EDTA and EGTA, both of which bind Hg2+ with very high affinity. To the contrary, the addition of these two chelating agents potentiates Hg2+ inhibition of tubulin polymerization. Results herein show that HgEDTA and HgEGTA inhibit tubulin polymerization by disrupting the interaction of GTP with the E-site of brain beta-tubulin, an obligatory step in the polymerization of tubulin. Both HgEDTA and HgEGTA, but not free Hg2+, prevented binding of [32P]8N3GTP, a photoaffinity nucleotide analog of GTP, to the E-site and displaced bound [32P]8N3GTP at low micromolar concentrations. This complete inhibition of photoinsertion into the E-site occurred in a concentration- and time-dependent fashion and was specific for Hg2+ complexes of EDTA and EGTA, among the chelating agents tested. Given the ubiquity of Hg2+ in the environment and the widespread use of EDTA in foodstuffs and medicine, these mercury complexes may pose a potentially serious threat to human health and play a role in diseases of the neuronal cytoskeleton. |
| Databáze: | OpenAIRE |
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