Fluoromevalonate acts as an inhibitor of insect juvenile hormone biosynthesis

Quistad, Gary B.; Cerf, David C.; Schooley, David A.; Staal, Gerardus B.

doi:10.1038/289176a0

Cited by 102 publications

(44 citation statements)

References 10 publications

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“…114) Kuwano and coworkers discovered several 1,5-disubstituted imidazole derivatives with anti-JH activity to the silkworm Bombyx mori. 115,116) The most active compounds are KK-22, KK-42 and KK-98.…”

Section: Inhibitors Of Biosynthetic Enzymesmentioning

confidence: 99%

Insect juvenile hormone action as a potential target of pest management

Minakuchi

Riddiford

2006

J. Pestic. Sci.

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Juvenile hormone (JH) is a sesquiterpenoid hormone that regulates growth and development in insects. Since JH is a hormone specific to insects and other arthropods, compounds disrupting JH action in insects are expected to be ideal insecticides with low toxicity to non-target organisms. Many natural or synthetic analogs with JH-like or anti-JH activity have been identified, and some potent JH mimics have been used as insecticides. Recent studies on the enzymes in JH biosynthetic and metabolic pathways should be helpful for the discovery of more potent analogs and for the establishment of new means of pest management using recombinant DNA technology. © Pesticide Science Society of Japan Keywords: juvenile hormone (JH), insect metamorphosis, insect growth regulators, biosynthesis and metabolism of JH. Review* To whom correspondence should be addressed. E-mail: chieka_minakuchi@yahoo.com © Pesticide Science Society of Japan doptera. 17,18) Higher Diptera such as D. melanogaster and the blowfly Calliphora vomitoria produce JH III bisepoxide. 19,20) A small amount of methyl farnesoate, a precursor of JH III, was found in cockroach embryos and larvae. [20][21][22] Methyl farnesoate has also been identified in crustaceans 23) and is thought to have a JH-like action in female reproduction. 24)12Ј-OH JH III identified from the corpora allata of the African locust Locusta migratoria migratorioides was reported to exhibit JH activity when a high dose of this compound was topically applied to Tenebrio pupae. 25,26) Biosynthesis, Transport and Metabolism of Juvenile HormoneIn insects, JH is synthesized in the corpora allata via the mevalonate pathway (Fig. 2).27) The mevalonate pathway also exists in mammals and plants, and the early steps from acetylCoA to farnesyl diphosphate are conserved among these organisms. Importantly, insects and other arthropods do not synthesize cholesterol de novo but have to acquire it from dietary sources because they lack the genes encoding squalene synthase and other subsequent enzymes of the sterol branch. 28,29) Another peculiarity of the mevalonate pathway in insects is the capacity to synthesize JH via the isoprenoid branch.The genes encoding the enzymes in the mevalonate pathway from acetyl-CoA to farnesyl diphosphate have been identified in the genome of D. melanogaster and the malaria mosquito Anopheles gambiae, and in an EST library of the pine engraver Ips pini.27) However, it has been difficult to identify the genes encoding enzymes from farnesyl diphosphate to JH

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Section: Inhibitors Of Biosynthetic Enzymesmentioning

confidence: 99%

Insect juvenile hormone action as a potential target of pest management

Minakuchi

Riddiford

2006

J. Pestic. Sci.

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“…The evidence for potential HMG CoA reductase regulation of JH synthesis has been derived from characterization of isolated corpora allata, the principal site of JH synthesis, of the tobacco hornworm. These studies have shown that JH synthesis can be blocked by mevalonate analogs (37) and competitive inhibitors of HMG CoA reductase (33) but is stimulated 100-fold by the addition of a key JH intermediate derived from mevalonate, farnesenic acid (45). Although the tobacco hornworm evidence suggests that the availability of mevalonate is essential for JH synthesis, studies in the cockroach corpora allata suggest that HMG CoA reductase may not be rate limiting for JH synthesis (18).…”

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confidence: 99%

Developmental and metabolic regulation of the Drosophila melanogaster 3-hydroxy-3-methylglutaryl coenzyme A reductase.

Gertler¹,

Chiu²,

Richter-Mann³

et al. 1988

Mol. Cell. Biol.

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The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in Drosophila melanogaster synthesizes mevalonate for the production of nonsterol isoprenoids, which are essential for growth and differentiation. To (Mr, 98,165) that was similar to the hamster HMG CoA reductase. The C-terminal region had 56% identical residues and the N-terminal region had 7 potential transmembrane domains with 32 to 60% identical residues. In hamster HMG CoA reductase, the membrane regions were essential for posttranslational regulation. Since the Drosophila enzyme is not regulated by sterols, the strong N-terminal similarity was surprising. Two HMG CoA reductase mRNA transcripts, -3.2 and 4 kilobases, were differentially expressed throughout Drosophila development. Mevalonate-fed Schneider cells showed a parallel reduction of both enzyme activity and abundance of the 4-kilobase mRNA transcript.Cholesterol is important for structural purposes in the membranes of vertebrates, but recent studies have also elucidated its role in regulating the expression of certain genes (5). The rate-controlling enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, is regulated by cholesterol in a complex pattern with both transcriptional (28, 34) and posttranslational (8, 19) mechanisms. As a typical housekeeping gene, the HMG CoA reductase gene is usually transcriptionally active. Its steady-state activity is subject to multivalent feedback suppression (4) by at least two classes of metabolic products derived from its immediate product, mevalonate. Cholesterol, the major mevalonate-derived product of mammalian cells, suppresses both HMG CoA reductase activity and its mRNA levels in cultured cells (10) and rat liver (26). Pretreatment of cells with cholesterol also prevented transcription from the gene in isolated nuclei (28), and the hamster HMG CoA reductase promoter remained cholesterol sensitive when transfected into cultured cells (34). Posttranslational regulation was revealed by the accelerated degradation of the enzyme in response to exogenous cholesterol (8). Thus, cholesterol has regulatory effects in both the nucleus and cytoplasm.Owing to the rapid and high conversion of mevalonate to sterols in mammals, it has been difficult to assess the sterol-independent regulatory pathway of HMG CoA reductase. Studies of this pathway suggested that the basal regulation was mediated by unidentified nonsterol mevalonate derivatives (16,47 Like the mammalian enzyme, the HMG CoA reductase of cultured Drosophila cells (Kc and Schneider cells) appears to be a microsomal enzyme whose activity is modulated by the addition of exogenous mevalonate. In contrast to the hamster enzyme, exogenous sterols have no effect upon the Drosophila HMG CoA reductase (3,32,43) and thus allow a clear separation of the sterol and nonsterol regulatory pathways. Since insects lack the ability to synthesize sterols and their HMG CoA reductase is insensitive to sterol regulation, one might conclude that insects either lost or neve...

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“…For example, inhibition of mevalonate kinase may provide an alternative means to statin drugs for the regulation of cholesterol synthesis 1,[15][16][17] and as insecticides which target juvenile hormone biosynthesis 18 . There is also interest in inhibiting bacterial GHMP kinases for the development of novel antibiotics 19 , and galactokinase inhibition has been proposed as a therapy for type I galactosemia 20 .…”

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confidence: 99%