Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acrylamide (ACR) is an environmental toxicant and prototypic tool for studying mechanisms of peripheral neuropathies. Reductions in fast anterograde axonal transport (faAXT) are thought to be a critical step leading to axonal degeneration. Kinesin and microtubules (MT) were evaluated as molecular sites of action using an in vitro MT motility assay. The number of locomoting MT which lifted from a bed of kinesin (MT detachments or MTD), increased from 7% in controls to 80, 89, and 100% following preincubation of kinesin (37 degrees C, 20 min) with 0.1, 0.5, or 1.0 mM ACR, respectively; rates were variably reduced by as much as 20%. Similar alterations were observed with N-ethylmaleimide. A non-neurotoxic analogue, propionamide (1mM), had no effect on either parameter. Preincubation of taxol-stabilized MT with ACR produced a dose-dependent increase in MTD but no changes in rate. We conclude that kinesin and MT are covalently modified by ACR resulting in reduced affinity for each other. The greater sensitivity of kinesin indicates that a primary cause of transient, ACR-induced reductions in faAXT is covalent modification of kinesin. Such reductions in faAXT may be sufficient to produce axonal degeneration. Further, ACR may prove useful as a pharmacological tool to decipher the complex mechanics of kinesin-MT interactions.
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PMID:Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility. 889

The microtubule (MT) motor protein kinesin is a vital component of cells and organs expressing acrylamide (ACR) toxicity. As a mechanism of its potential carcinogenicity, we determined whether kinesins involved in cell division are inhibited by ACR similar to neuronal kinesin [Sickles, D.W., Brady, S.T., Testino, A.R., Friedman, M.A., and Wrenn, R.A. (1996). Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility. Journal of Neuroscience Research 46, 7-17.] Kinesin-related genes were isolated from rat testes [Navolanic, P.M., and Sperry, A.O. (2000). Identification of isoforms of a mitotic motor in mammalian spermatogenesis. Biology of Reproduction 62, 1360-1369.], their kinesin-like proteins expressed in bacteria using recombinant DNA techniques and the effects of ACR, glycidamide (GLY) and propionamide (a non-neurotoxic metabolite) on the function of two of the identified kinesin motors were tested. KIFC5A MT bundling activity, required for mitotic spindle formation, was measured in an MT-binding assay. Both ACR and GLY caused a similar concentration-dependent reduction in the binding of MT; concentrations of 100 microM ACR or GLY reduced its activity by 60%. KRP2 MT disassembling activity was assayed using the quantity of tubulin disassembled from taxol-stabilized MT. Both ACR and GLY inhibited KRP2-induced MT disassembly. GLY was substantially more potent; significant reductions of 60% were achieved by 500 microM, a comparable inhibition by ACR required a 5 mM concentration. Propionamide had no significant effect on either kinesin, except KRP2 at 10 mM. This is the first report of ACR inhibition of a mitotic/meiotic motor protein. ACR (or GLY) inhibition of kinesin may be an alternative mechanism to DNA adduction in the production of cell division defects and potential carcinogenicity. We conclude that ACR may act on multiple kinesin family members and produce toxicities in organs highly dependent on microtubule-based functions.
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PMID:Acrylamide effects on kinesin-related proteins of the mitotic/meiotic spindle. 1754 Apr 27