Tubulin/microtubules

Lewy bodies are typical in neuronal degeneration, which is accompanied by the presence of these eosinophilic intracellular inclusions of 5-25 pm diameter in a proportion of still surviving neurons. Lewy bodies contain neurofilament, tubulin, microtubule-associated proteins 1 and 2, and gelsolin, an actin-modulating protein. 

Colchicine (6) is used in the treatment of a broad range of diseases including acute gout and Mediterranean fever [28] and induces depolymerization of tubulin. This compound (6) distorts the tubulin/microtubule equilibrium by binding to the tubulin dimer and halting mitosis in the metaphase. The reason this approach is such a successful target in cancer therapy is that... 

Microtubule a hollow rod formed from the protein tubulin. Microtubules form part of the cytoskeleton of cells as well as cilia and flagella. 

Tubulin/Microtubule activities" Activities with cultured ceils h... 

Fig. 4 Tubulin microtubules and Zn-sheets. The paired series of images show these polymeric forms of tubulin from different views. Top - parallel (in line) with the protofilament axis. Middle - 45° to the pf axis. Bottom - perpendicular to the pf axis (for the microtubule, this is the luminal view)...

Since the discovery 117) of its action on tubulin 118) (the protein which, in the form of microtubules, constitutes the mitotic spindle), taxol has been of great utility to biologists. Numerous publications, not all of which need be cited here, describe the use of taxol for the isolation of tubulin from cellular preparations in which the concentration of this protein is too low to permit its polymerization, as in the pancreas 119) or the vegetal domain 120). Taxol has permitted not only the discovery of new microtubules in the Xenopus oocyte cortex 121) but also the study of the role of microtubules in certain cellular processes owing to its lack of destructive effects, in contrast to other known spindle poisons such as colchicine or vinblastine (722). Among other problems, taxol has helped in studies of the influence of the tubulin-microtubule equilibrium on the fluidity of platelet membranes 123) and of the function of the meiotic spindle in spermatocytes 124). 

Figure 34.23. Tubulin. Microtubules can be viewed as an assembly of a-tubulin - P-tubulin dimers. The structures of a-tubulin and P-tubulin are quite similar each includes a P-loop NTPase domain (purple shading) and a bound guanine nucleotide.

Microtubule— A hollow protein cylinder, about 25 nanometers in diameter, composed of subunits of the protein tubulin. Microtubules grow in length by the addition of tubulin subunits at the end and are shortened by their removal. 

Lewy body Intracytoplasmic neuronal inclusions which are intensely eosinophilic under routine haematoxylineosin stain. Immuocytochemically, Lewy bodies share epitopes with phos-phorylated and non-phosphorylated a-synclein, neurofilament subunits, tubulin, microtubule-associated protein 1 and 2, and... 

These are Ca -binding proteins found in the brain and the central nervous system, which belong to the same branch of the calmodulin family as the intestinal proteins, to which they are closely related. Both contain one variant and one normal " site for Ca . The SlOO protein exists in two forms, a and b. Binding of calcium results in conformational change. The SlOOb protein also binds two Zn ions, with conformational change, and with higher affinity than Ca. Zn is involved with the tubulin microtubule system in brain. SlOOb may be associated with this process. 

The role of cytoskeletal tubulins in the mode of action and mechanism of drug resistance to benzimidazoles has been reviewed by Lacey [111], who also supports the above hypothesis proposing a close relationship between tubulin-microtubules and other sites of the benzimidazole action. It is believed that inhibition of glucose uptake, fumarate-reductase activity or neuromuscular activity are dependent on inhibition of polymerisation of tubulins to microtubules by benzimidazoles. The inhibition of tubulins by benzimidazoles is so pronounced that it is postulated that even the hatching of eggs of H. controtus is a microtubule dependent process [240]. 

FIGURE 20-11 Dynamic instability model of microtubule growth and shrinkage. GTP-bound a(3-tubulin subunits (red) add preferentially to the (-t) end of a preexisting microtubule. After incorporation of a subunit, the GTP (red dot) bound to the (i-tubulin monomer is hydrolyzed to GDP Only microtubules whose (+) ends are associated with GTP-tubulin (those with a GTP cap) are stable and can serve as primers for the polymerization of additional tubulin. Microtubules with GDP-tubulin (blue) at the (+) end (those with a GDP cap) are rapidly depolymerized and may disappear within 1 minute. At high concentrations of unpolymerized GTP-tubulin, the rate of addition of tubulin is faster than the rate of hydrolysis of the GTP bound in the microtubule or the rate of dissociation of GTP-tubulin from microtubule ends thus the microtubule grows. At low concentrations of unpolymerized GTP-tubulin, the rate of addition of tubulin is decreased consequently, the rate of GTP hydrolysis exceeds the rate of addition of tubulin subunits and a GDP cap forms. Because the GDP cap is unstable, the microtubule end peels apart to release tubulin subunits. [See T Mitchison and M. Kirschner, 1984, Nature 312 237 ... 

Many drugs that Inhibit mitosis bind specifically to tubulin, microtubules, or both. What diseases are such drugs used to treat Functionally speaking, these drugs can be divided into two groups based on their effect on microtubule assembly. What are the two mechanisms by which such drugs alter microtubule assembly ... 

Substances able to interact with tubulin/microtubule system represent a potential inhibitor of cell replication. 

Cytoskeleton. The cytoskeleton is a flexible fibrous protein support system that maintains the geometry of the cell, fixes the position of organelles, and moves compounds within the cell or the cell itself. It is composed principally ofactin microfilaments, intermediate filaments, tubulin microtubules, and their attached proteins. 

Rouz D, Hadi HA, Thoret S, Guenard D, Thoison O, Pais M, Sevenet T (2000) Structure-Activity Relationship of Polyisoprenyl Benzophenones from Garcinia pyrifera on the Tubulin/Microtubule System. J Nat Prod 63 1070... 

David B, Sevenet T, Thoison O, Awang K, Pais M, Wright M, Guenard D (1997) Hemisynthesis of Rhazinilam Analogues Structure-Activity Relationships on Tubulin-Microtubule System. Bioorg Med Chem Lett 7 2155... 

Class Ilb subtypes 6 and 10 are characterised by a duplication of their catalytic domain the best-characterised isoform is HDAC6, which deacetylates tubulin, microtubules, and HSP90. " Little is known about HDACl 1. 

Taxol is a complex diterpene from the yew tree, especially the Pacific yew—Taxus brevifolia (Taxaceae). Taxol and its derivatives are used as prescription drugs for cervical and breast tumours (Lenaz and De Furia 1993). It has an antimitotic effect, associated with an interaction of taxol with the tubulin-microtubule system (Hamburger and Hostettmann 1991). 

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