A83543A-D, unique fermentation-derived tetracyclic macrolides

Kirst, Herbert A.; Michel, K. H.; Martin, James W.; Creemer, Lawrence C.; Chio, Eddie Hang; Yao, Raymond C.; Nakatsukasa, Walter M.; Boeck, L. D.; Occolowitz, John L.; Paschal, Jonathan W.; Deeter, Jack B.; Jones, Noel D.; Thompson, Gary D.

doi:10.1016/s0040-4039(00)93474-9

Cited by 118 publications

(101 citation statements)

References 6 publications

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“…23 The major component in the fermentation is spinosyn A (1), whose structure is depicted in Figure 1. 24 The structure was determined by NMR, MS and X-ray analyses and comprises a tetracyclic polyketide aglycone to which is attached a neutral saccharide substituent (2,3,4-tri-O-methyla-L-rhamnosyl) on the C-9 hydroxyl group and an aminosugar moiety (b-D-forosaminyl) on the C-17 hydroxyl group (Figure 1). The absolute configuration was established by the co-identity of forosamine, obtained by hydrolysis of spinosyn A, with D-forosamine obtained from hydrolysis of spiramycin.…”

Section: Structure and Synthesismentioning

confidence: 99%

“…The absolute configuration was established by the co-identity of forosamine, obtained by hydrolysis of spinosyn A, with D-forosamine obtained from hydrolysis of spiramycin. 24 This spinosyn tetracyclic ring system composed of a cis-anti-trans-5,6,5-tricyclic moiety fused to a 12-membered lactone is a unique ring system. The most closely related structures seem to be the ikarugamycincapsimycin group, although they have a different substituent pattern and the opposite absolute stereochemistry of their 5,6,5 ring system, which is fused to a macrolactam containing an embedded tetramic acid.…”

Section: Structure and Synthesismentioning

confidence: 99%

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The spinosyn family of insecticides: realizing the potential of natural products research

Kirst¹

2010

J Antibiot

287

163

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The spinosyns are a large family of unprecedented compounds produced from fermentation of two species of Saccharopolyspora. Their core structure is a polyketide-derived tetracyclic macrolide appended with two saccharides. They show potent insecticidal activities against many commercially significant species that cause extensive damage to crops and other plants. They also show activity against important external parasites of livestock, companion animals and humans. Spinosad is a defined combination of the two principal fermentation factors, spinosyns A and D. Structure-activity relationships (SARs) have been extensively studied, leading to development of a semisynthetic second-generation derivative, spinetoram. The spinosyns have a unique mechanism of action (MOA) involving disruption of nicotinic acetylcholine receptors. When compared with many other insecticides, the spinosyns generally show greater selectivity toward target insects and lesser activity against many beneficial predators as well as mammals and other aquatic and avian animals. Their insecticidal spectrum, unique MOA and lower environmental effect make them useful new agents for modern integrated pest management programs. As a result, this work has received U S Presidential Green Chemistry Challenge Awards.

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Section: Structure and Synthesismentioning

confidence: 99%

Section: Structure and Synthesismentioning

confidence: 99%

The spinosyn family of insecticides: realizing the potential of natural products research

Kirst¹

2010

J Antibiot

287

163

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“…Permethylated L-rhamnose is not frequently found as a sugar moiety in glycosylated, bioactive natural compounds. As far as we know, this completely O-methylated sugar occurs only in the molecule studied in this work, elloramycin, produced by S. olivaceus (11), and in the macrolide insecticide spinosyn produced by Saccharomyces spinosa (29). From the elloramycin producer, we have identified three methyltransferase-encoding genes (elmMI, elmMII, and elmMIII) in a cosmid that contains part of the elloramycin gene cluster.…”

Section: Discussionmentioning

confidence: 89%

Deoxysugar Methylation during Biosynthesis of the Antitumor Polyketide Elloramycin by Streptomyces olivaceus

Patallo

Blanco

Fischer

et al. 2001

Journal of Biological Chemistry

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The anthracycline-like polyketide drug elloramycin is produced by Streptomyces olivaceus Tü 2353. Elloramycin has antibacterial activity against Gram-positive bacteria and also exhibits antitumor activity. From a cosmid clone (cos16F4) containing part of the elloramycin biosynthesis gene cluster, three genes (elmMI, elmMII, and elmMIII) have been cloned. Sequence analysis and data base comparison showed that their deduced products resembled S-adenosylmethionine-dependent O-methyltransferases. The genes were individually expressed in Streptomyces albus and also coexpressed with genes involved in the biosynthesis of L-rhamnose, the 6-deoxysugar attached to the elloramycin aglycon. The resulting recombinant strains were used to biotransform three different elloramycin-type compounds: Lrhamnosyl-tetracenomycin C, L-olivosyl-tetracenomycin C, and L-oleandrosyl-tetracenomycin, which differ in their 2-, 3-, and 4-substituents of the sugar moieties. When only the three methyltransferase-encoding genes elmMI, elmMII, and elmMIII were individually expressed in S. albus, the methylating activity of the three methyltransferases was also assayed in vitro using various externally added glycosylated substrates. From the combined results of all of these experiments, it is proposed that methyltransferases ElmMI, ElmMII, and Elm-MIII are involved in the biosynthesis of the permethylated L-rhamnose moiety of elloramycin. ElmMI, ElmMII, and ElmMIII are responsible for the consecutive methylation of the hydroxy groups at the 2-, 3-, and 4-position, respectively, after the sugar moiety has been attached to the aglycon.A number of important bioactive compounds are produced by actinomycetes. Particularly, the streptomycetes are responsible for the biosynthesis of most of the bioactive compounds clinically useful or with application in veterinary and animal husbandry. Many of them are glycosylated compounds and, in this case, the biological activity is usually correlated with the presence of the sugars, being in some cases essential for activity. Most of these sugars belong to the large family of 6-deoxyhexoses (6DOHs), 1 which form part of a great number of natural products, and at least 70 different 6DOHs have been identified in various metabolites (1-3). In recent years, a number of genes encoding deoxysugar biosynthetic enzymes from antibiotic-producing microorganisms have been characterized. The first and common step in most 6DOH biosynthesis is the activation of D-glucose 1-phosphate into TDP D-glucose in a reaction catalyzed by a glucose-1-phosphate:TTP thymidylyl transferase. Then a key dehydration step takes place, by the action of a TDP-D-glucose-4,6-dehydratase, generating TDP-D-4-keto-6-deoxyglucose, a key intermediate of the 6DOH biosynthesis. In this step, the 6-position of the sugar gets deoxygenated, and the typical 5-methyl group (ϭC-6) is generated that will remain in the structure of all 6DOHs. These two "initial" enzymes are quite well conserved in many pathways, thus facilitating the use of the corresponding genes a...

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“…Microorganisms are also used to produce biopesticide active substances from lignocellulosic materials. Two species of the bacterial genus Saccharopolyspora produce spinosyns through the fermentation of carbohydrates or vegetative media (Kirst et al 1991;Lewer et al 2009). Some common natural chemical compounds are included in Table 1 and Table 2.…”

Section: Modes and Mechanisms Of Action To Avoid Pest Resistancementioning

confidence: 99%

Biopesticides from Natural Products: Current Development, Legislative Framework, and Future Trends

Villaverde¹,

Sandín‐España²,

Sevilla-Morán³

et al. 2016

BioResources

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The importance of biomass as a source of chemicals, biofuels, and energy is widely accepted. Currently, the attention is mainly focused on the valorisation of by-products from lignocellulosic materials. Chemical compounds derived from plants and microorganisms that provide good protection for crops against weeds, pests, and diseases (biopesticide active substances) have been used to formulate pesticides. Their use is increasingly encouraged by new pesticide regulations that discourage the use of harmful active substances. This article reviews the current and future situation of biopesticides, especially natural chemical products, and focuses on their potential within the European pesticide legislative framework. Moreover, this article highlights the importance of the different modes/mechanisms of action of the active substances obtained from natural sources, the role of chemistry in biopesticide development, and how the adoption of integrated pest management practices contributes to a greater trend towards biopesticides.

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A83543A-D, unique fermentation-derived tetracyclic macrolides

Cited by 118 publications

References 6 publications

The spinosyn family of insecticides: realizing the potential of natural products research

The spinosyn family of insecticides: realizing the potential of natural products research

Deoxysugar Methylation during Biosynthesis of the Antitumor Polyketide Elloramycin by Streptomyces olivaceus

Biopesticides from Natural Products: Current Development, Legislative Framework, and Future Trends

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