Pesticides: Insecticides and Fungicides Are Chitin Synthesis Inhibitors

Leighton, Terrance; Marks, Edwin P.; Leighton, Frances

doi:10.1126/science.213.4510.905

Cited by 100 publications

(35 citation statements)

References 13 publications

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“…This interpretation would be consistent with the proposal of Leighton et al (1981), who suggested that diflubenzuron may inhibit a protease-induced activation of the zymogen form of chitin synthase. It would be consistent also with the results of Horst (1981), who found that microsomal preparations from larvae of the brine shrimp (Artemia salina) show reduced capacity for chitin synthesis following pre-incubation with diflubenzuron.…”

Section: Discussionsupporting

confidence: 80%

“…Similarly, in a microsomal chitin synthase system prepared from extracts of larvae of the brine shrimp (Artemia salina), inhibition was obtained only after preincubation of the system with diflubenzuron (Horst 1981). Recently, Leighton et al (1981) proposed that diflubenzuron acts indirectly on chitin synthase, by inhibiting a proteolytic enzyme required for the activation of chitin synthase from a zymogen form.…”

Section: Introductionmentioning

confidence: 99%

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Integumental Chitin Synthase Activity in Cell-free Extracts of Larvae of the Australian Sheep Blowfly, Lucilia cuprina, and Two Other Species of Diptera

Turnbull¹,

Howells²

1983

Aust. Jnl. Of Bio. Sci.

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Chitin synthase activity has been demonstrated in crude homogenates of larval integuments from L. cuprina and in similar preparations from Musca domestica and Calliphora erythrocephala. This is the first report of an insect integumental chitin synthase. This activity brings about the incorporation of radioactivity from UDP-N-acetyl-[14C]glucosamine into an ethanol-and alkali-insoluble form. A major part of this labelled product has been characterized as chitin by its insolubility in alkali, resistance to degradation by proteases and its susceptibility to digestion by chitinase and RCI. Most of the radioactivity solubilized during digestion by chitinase co-migrates with N-acetylglucosamine, glucosamine and chitobiose during paper chromatography. Some radioactivity also becomes incorporated into non-chitin products in this system. There is substantial evidence that incorporation is not brought about by whole epidermal cells or by microbial contamination in the homogenates. The extent of incorporation obtained with the homogenates is limited by the presence of degradative enzymes which rapidly break down the substrate (UDP-N-acetylglucosamine). The incorporation was partially inhibited (50-70%) by both polyoxin-D (apparent Ki 0'04I1M) and diftubenzuron (apparent . This is the first report of a cell-free chitin-synthesizing system derived from insect tissue which is sensitive to inhibition by diftubenzuron.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Integumental Chitin Synthase Activity in Cell-free Extracts of Larvae of the Australian Sheep Blowfly, Lucilia cuprina, and Two Other Species of Diptera

Turnbull¹,

Howells²

1983

Aust. Jnl. Of Bio. Sci.

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“…In recent studies with cellfree insect extracts which exhibit chitin synthase activity (Cohen and Casida 1980b;Mayer et al 1980) diflubenzuron was found to have no inhibitory effect. Leighton et al (1981) have proposed that diflubenzuron acts indirectly on chitin synthase by inhibiting a proteolytic enzyme required for its activation from the zymogen form.…”

Section: Discussionmentioning

confidence: 99%

Effects of Several Larvicidal Compounds on Chitin Biosynthesis by Isolated Larval Integuments of the Sheep Blowfly Lucilia cuprina

Turnbull¹,

Howells²

1982

Aust. Jnl. Of Bio. Sci.

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Isolated whole integuments from L. cuprina larvae rapidly incorporate radioactivity from both N-acetyl[I-'4C]glucosamine and [1-'4C]glucosamine into alkali-insoluble material, a reaction which does not require preincubation of the tissue with /i-ecdysone. The labelled product was degraded to N-acetylglucosamine during digestion with chitinase, establishing that it consists mainly of chitin. Incorporation was inhibited by polyoxin-D (Iso, 6 x 10-7 M) and diflubenzuron (Iso, 7 x 10-7M) but was not inhibited to any marked extent by isoprothiolane, Vetrazin or a-methyl-DOPA. The effectiveness of diflubenzuron as an inhibitor of chitin synthesis in this system (Iso, 7 x 10-7 M) correlates well with its potency as a larvicide (LDso, 2·1 x 10-6 M), providing additional support for the proposal that this compound kills larvae by interfering with chitin deposition in the cuticle. Polyoxin-D was much more effective as an inhibitor of chitin synthesis (Iso, 6 x 10-7 M) than as a larvicide (LDso, 2·0x 10-5 M). It was established that the final intermediate of chitin biosynthesis (UDP-N-acetylglucosamine) was formed in the isolated integuments in the presence of diflubenzuron and polyoxin-D. It seems likely therefore that both compounds interfere with the final polymerization step of the chitin biosynthesis pathway.

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“…Although the authors did not recognize that an inhibition of chitin synthesis was responsible for these effects, the potential for these agents as pesticides and fungicides was ultimately recognized and described. While the action of the benzoylphenyl ureas on insect cuticles was claimed to be identical to that seen with polyoxin D (227), others thought that the specific effects of this class of agent were a result of an inhibition of serine protease activity that blocked activation of the chitin synthetase zymogen (150). These and other chymotrypsin inhibitors were demonstrated to prevent chitin synthesis in a cockroach system.…”

Section: Compounds Active Against Fungal Cell Walls Inhibitors Of Chimentioning

confidence: 99%

Compounds active against cell walls of medically important fungi

Hector

1993

Clin Microbiol Rev

215

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A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

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Pesticides: Insecticides and Fungicides Are Chitin Synthesis Inhibitors

Cited by 100 publications

References 13 publications

Integumental Chitin Synthase Activity in Cell-free Extracts of Larvae of the Australian Sheep Blowfly, Lucilia cuprina, and Two Other Species of Diptera

Integumental Chitin Synthase Activity in Cell-free Extracts of Larvae of the Australian Sheep Blowfly, Lucilia cuprina, and Two Other Species of Diptera

Effects of Several Larvicidal Compounds on Chitin Biosynthesis by Isolated Larval Integuments of the Sheep Blowfly Lucilia cuprina

Compounds active against cell walls of medically important fungi

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