Herbicidal interference with microtubules

It has been known for some time that members of the dinitroaniline and N-phenylcarbamate classes of herbicides interfere with the structure and functions of microtubules. Representative structures of these herbicides are presented in Table 10.1.

Dinitroanilines. Trifluralin, oryzalin and pendimethalin are widely used pre-emergence herbicides in dicot crops such as cotton and soybean for the control of grasses, and useful selectivity in wheat is evident. At concentrations as low as 1 |M, weeds show characteristic reductions in root length and swollen root tips, an effect identical to those obtained when treating seedlings with the well-known mitotic disruptor colchicine. Ultrastructural analysis reveals cells arrested at prometaphase (Vaughn and Lehnen, 1991) and so no metaphase or later stages are observed. Instead, a nuclear membrane reforms around the chromosomes and the nucleus appears highly lobed. No spindle microtubules are evident in treated cells and cortical microtubules are also affected, with the result that cells appear square-shaped rather than rectangular, explaining the swollen appearance of the root tips.

Recently, Tresch and colleagues (2005) have demonstrated that the cyanoacrylates (CAj and CA2: Figure 10.5) are a new chemical class of herbicides with the same mechanism of action as the dinitroanilines, interacting with the a--ubulin binding site to prevent tubulin polymerisation.

Both dinitroanilines and colchicine inhibit microtubule assembly by forming a tubule-herbicide complex that disrupts polymerisation and hence microtubule assembly. In so doing, the depolymerisation process continues, shortening the microtubules until they are eventually undetectable. Unlike colchicine, the dinitroaniline herbicides do not inhibit tubulin polymerisation in animals, nor disrupt cell division in animal cells. At higher concentrations the dinitroaniline can also inhibit photosynthetic electron flow and oxidative phosphorylation.

These herbicides act by binding to a, P--ubulin dimers. The incorporation of dimer-herbicide complexes into a polymerising tubulin filament is thought to block further polymerisation and to cause microtubule disruption. It follows that any mutation causing changes in the amino acid content of tubulin may alter herbicide binding and could lead to herbicide resistance (Anthony et al., 1998).

The fact that the herbicides display low affinity for animal tubulins renders them relatively environmentally benign.

Table 10.1 Structures of herbicides that interfere with microtubule assembly or function.

Table 10.1 Structures of herbicides that interfere with microtubule assembly or function.

R-i R2 Common name

Cl CH2C=CCH2Cl barban

H CHCH3CONHC2H5 carbetamide

Cl CH(CH3)2 chlorpropham

H CH(CH3)2 Cropham

(c) others

N-phenylcarbamates . The phenylcarbamates also disrupt mitosis and inhibit photo-synthetic electron flow and oxidative phosphorylation at high concentrations. In this case, microscopy reveals intact microtubules but chromosomal abnormalities. Chromosome movement during anaphase normally generates two sites at opposite poles of the cell, but in tissues treated with herbicide, three or more chromosome sites are observed after anaphase. Nuclear membranes then form around each group of chromosomes, and abnormal phragmoplasts organise irregularly shaped, abnormal cell walls. The proposed mechanism is the interference of the spindle microtubule-organising centres, fragmenting them throughout the cell, giving rise to the symptoms of multi-polar cell division. How this is achieved and the sites of action are unknown. Barban, carbetamide, propham and chlorpropham all interfere with mitosis in this manner.

These herbicides have been known since the 1950s and show useful activity against grasses. Nowadays, chlorpropham is principally used for the suppression of sprout growth in stored potato tubers, due to the inhibition of sprout cell division.

Others. Chlorthal-dimethyl (DCPA) is widely used in turf grasses. It appears to block cell plate formation in susceptible species, via the disruption of phragmoplast microtubule organisation and production, by an unknown mechanism. There is some indication that CDK phosphatase activity is inhibited by endothal, thus preventing G2/M transition (Ayaydin et al. . 2000) . Amiprophos -methyl results in a loss of microtubules and gives similar symptoms to the dinitroanilines. Propyzamide acts in a different fashion to those described so far, such that small microtubules rather than none at all result from treatment with this herbicide. It binds directly to the tubulin, preventing microtubule assembly (Akashi, et al, 1988). Dithiopyr acts similarly to propyzamide, but binds to a microtubule-associated protein (MAP) of molecular weight 65kDa, rather than to tubulin. Vaughn and Lehnen ) 1991) are of the view that dithi-opyr interacts with a MAP involved in microtubule stability, resulting in shortened microtubules.

Clearly, there remain many unanswered questions regarding microtubule assembly and function in plant cell division. The aforementioned herbicides may provide useful probes to study microtubule biochemistry and further work may yield additional novel herbicide targets.

N •—^

3L T- _S_

Figure 10.6 The effect of treatment with 0.1 g ai L-1 imazethapyr on mitotic divisions of potato (Solanum tuberosum) cv. Cara tuber root tips using aerated liquid media. Data are means of 6 replicates ± standard error. Treated and control samples were significantly different at every point (p < 0.01) (from Spackman and Cobb, 1999).

Intriguingly, it has also been observed that members of the imidazolinone and sulfonylurea herbicide families inhibit entry into mitotic cell division. Rost (1984) found that chlorsulfuron inhibited the cell cycle progression at G2 and G1 transitions and also demonstrated a similar effect of imidazolinones (Rost et al, 1990). Both herbicide families inhibit acetolactate synthase (ALS, see Chapter 9) in the synthesis of the branched-chain amino acids (valine, leucine, isoleucine) and cell cycle inhibition can be reversed by the addition of these amino acids. This may imply a link between branched-chain amino acid biosynthesis and cell cycle entry, although the precise nature of this remains to be established.

Spackman and Cobb (1999) observed a rapid inhibition of cell division in potato root tips treated with imazethapyr. Significantly lower numbers of mitotically dividing cells were recorded after only 30 min incubation with 0.35 ||M imazethapyr (Figure 10.6). The commercialisation of this response as a novel, low-dose potato-sprout suppressant remains to be demonstrated.

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