Duhr EF, Pendergrass JC, Slevin JT & Haley BE

HgEDTA complex inhibits GTP interactions with the E-site of
brain beta-tubulin.

Toxicol Appl Pharmacol 122(2):273-280
(1993)

ABSTRACT: "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."

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