Further studies on the biosynthesis of the avermectins

Chen, Tom S.; Arison, Byron H.; Gullo, Vincent P.; Inamine, Edward

doi:10.1007/bf01574080

Cited by 26 publications

(14 citation statements)

References 7 publications

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“…5). CANE et al (1983) andCHEN et al (1988) demonstrated that the aglycone moiety of AVMs was built by the condensation of 5 propionates, 7 acetates and 1 starting unit, which is in the case of AVMs "a" formed from 2-methylbutyrate and in the case of "b" from isobutyrate. AVMs do not contain nitrogen in their molecule, however, the intermediates of amino acids metabolism can be sources of their precursors and, in this way, regulate their biosynthesis to a considerable extent.…”

Section: Production Ofavms On Amino Acids and Ammonium Sulfatementioning

confidence: 99%

Nitrogen regulation of avermectins biosynthesis in Streptomyces avermitilis in a chemically defined medium

Cimburková

Zima

Novák

et al. 1988

J. Basic Microbiol.

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The biosynthesis of avermectins was significantly affected by the nitrogen source used. The maximum yield of AVMs') was achieved in a chemically defined medium with ammonium sulfate as the sole nitrogen source. Higher concentrations of ammonia inhibited the production of AVMs without the inhibition of the growth. AVMs of the group B were prevailing in the complex until I5 mM ammonium sulfate. At higher concentrations, AVMs of the group A predominated. Of various amino acids tested, lysine and asparagine were found to be the best for the biosynthesis of AVMs. The concentration of most amino acids higher than 0.2% inhibited the production, while the mycelium was still growing. The biosynthesis of AVMs was completely suppressed by 15.2 m~ isoleucine, however, this inhibition was reversed by adding alanine at the beginning of cultivation.A considerable attention has recently been devoted to the regulation of biosynthesis of so called secondary metabolites by nitrogen containing substrates. In previous studies, e.g. of the biosynthesis of chlortetracycline, it has already been shown that some amino acids are metabolized to precursors (malonylCoA) forming a nitrogen free. nonaketide skeleton PODOJIL et al. 1973, BEHAL et al. 1979. The regulation of antibiotic biosynthesis by nitrogen compounds was reviewed by AHARONOWITZ (1980). These regulations were studied in producers of p-lactam antibiotics, e.g. Streptomyces clavuligerus (AHARONOWITZ and DEMAIN 1979, B R A~A et al. 1985 In the present work we studied the effect of nitrogen source on the biosynthesis of avermectins. These compounds have neither antibacterial nor antifungal activity, but they are excellent anthelmintics and insecticides. They are pentacyclic lactones with a disaccharide cr-L-oleandrose, which do not contain nitrogen in their molecule, although it is formally possible to derive their starting unit from isoleucine or valine (Fig. 1). Streptomyces avermitilis produces a complex of 8 avermectins consisting of 4 major (Al,, A,=, B1,, B,,) and 4 minor (Albl A,,, B,,, B2d components. As far as their efficiency is concerned Bla is the most interestmg compound.The production of avermectins was studied in a chemically defined medium where amino acids or ammonium sulfate were the only nitrogen source.') AVM = Avermectin

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Section: Production Ofavms On Amino Acids and Ammonium Sulfatementioning

confidence: 99%

Nitrogen regulation of avermectins biosynthesis in Streptomyces avermitilis in a chemically defined medium

Cimburková

Zima

Novák

et al. 1988

J. Basic Microbiol.

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“…The C-25 oxygen is most probably derived from the starter unit and that of the furan from molecular oxygen. The three methoxy groups derive from L-methionine and the oleandrose units from glucose [63,64].…”

Section: The Avermectinsmentioning

confidence: 99%

The Biosynthesis of Aliphatic Polyketides

Staunton

Wilkinson²

1998

Biosynthesis

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Aliphatic polyketides are a large family of natural products which exhibit an impressive range of biological activities. They are synthesised by a common pathway in which units derived from acetate, propionate and butyrate are condensed onto a growing chain, which is initiated from a range of structurally varied carboxylic acid starter units, in a process closely resembling fatty acid biosynthesis. The intermediates remain bound to the polyketide synthase (PKS) throughout multiple rounds of chain extension, and to a variable degree, reduction of the newly formed b-keto functionality. It is the manner in which each different PKS controls the number and type of extender units added, and the extent and stereochemistry of reduction at each cycle which gives rise to the diverse structural variation seen in this family of natural products. Furthermore, the aglycone product of the PKS may be modified by post-PKS enzymes, including glycosidases, methyltransferases, acylases and oxidative enzymes, to produce still greater diversity. In this article the development of the field will be exemplified by a detailed discussion of the archetypal example of erythromycin A biosynthesis. This will then be followed by further discussion of other relevant areas of research in this field.

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“…Avermectins contain a disaccharide of the methylated sugar oleandrose. The avermectin aglycone is synthesized by a polyketide pathway in which seven acetate and five propionate units are condensed to starting units of either 2-methylbutyrate ("a" components) or isobutyrate ("b" components) (9,12). After cyclization, the aglycone undergoes further modification including dehydration at C-22 and C-23, 0 methylation at C-5, and glycosylation at C-13.…”

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confidence: 99%

“…The biosynthesis of avermectin involves several post-macrolide-ring modifications including furan ring closure, reduction of the C-5 keto group, methylation of the C-5 hydroxy group, and glycosylation of the C-13 hydroxy group with oleandrose disaccharide (8,12,44 (32), similar to the 6 modular repeats in erythromycin (4,14,15). To the left of the PKS region maps the gene for avermectin C-5 B O-methyltransferase (47), and further to the left is an 8-kb region, designated Reg (Fig.…”

mentioning

confidence: 99%

“…Liquid medium for S. avernitilis was modified YEME (24) with 15 to 30% sucrose; solid media were YME-TE (27) for growth and sporulation, RM14 (31) for regeneration of transformants, and M9 (39) to test for prototrophy. Avermectin fermentations utilized seed medium (12) and modified medium B (6). Antibiotics used were ampicillin (100 jig/ml), kanamycin (30 ,ug/ml), chloramphenicol (12.5 Rg/ml) for E. coli, and thiostrepton (10 ,ug/ml) and neomycin (2 to 10 jig/ml) for S. avennitilis.…”

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confidence: 99%

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Deletion analysis of the avermectin biosynthetic genes of Streptomyces avermitilis by gene cluster displacement

1993

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Streptomyces avermitilis produces a group of glycosylated, methylated macrocyclic lactones, the avermectins, which have potent anthelmintic activity. A homologous recombination strategy termed gene cluster displacement was used to construct Neor deletion strains with defined endpoints and to clone the corresponding complementary DNA encoding functions for avermectin biosynthesis (avr). Thirty-five unique deletions of 0.5 to >100 kb over a continuous 150-kb region were introduced into S. avermitilis. Analysis of the avermectin phenotypes of the deletion-containing strains defined the extent and ends of the 95-kb avr gene cluster, identified a regulatory region, and mapped several avr functions. A 60-kb region in the central portion determines the synthesis of the macrolide ring. A 13-kb region at one end of the cluster is responsible for synthesis and attachment of oleandrose disaccharide. A 10-kb region at the other end has functions for positive regulation and C-5 0 methylation. Physical analysis of the deletions and of in vivo-cloned fragments refined a 130-kb physical map of the avr gene cluster region.

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Further studies on the biosynthesis of the avermectins

Cited by 26 publications

References 7 publications

Nitrogen regulation of avermectins biosynthesis in Streptomyces avermitilis in a chemically defined medium

Nitrogen regulation of avermectins biosynthesis in Streptomyces avermitilis in a chemically defined medium

The Biosynthesis of Aliphatic Polyketides

Deletion analysis of the avermectin biosynthetic genes of Streptomyces avermitilis by gene cluster displacement

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