The Role of Nutrition in the Synthesis of Actinomycin

Katz, Edward; Pienta, Phyllis; Sivak, Andrew

doi:10.1128/am.6.4.236-241.1958

Cited by 56 publications

(7 citation statements)

References 14 publications

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“…However, increasing the glucose concentration to 2% blocked the production of actinomycins. Glucose was previously reported to repress the transcription of the gene for hydroxykynureninase, which is involved in the formation of the main actinomycin precursor 4-MHA (26). Importantly, in our experiments the carbon source not only promoted the overall production levels, but also contributed to the chemical diversity of the actinomycins, including the production of actinomycin L. This coincided with the production of anthranilamide, an essential substrate to form this novel actinomycin variant.…”

Section: Discussionsupporting

confidence: 63%

“…Indeed, the production of actinomycins by Streptomyces spp. is strongly influenced by the carbon source, whereby the preferred carbon source varies from strain to strain (16,22,26,47,55). D-galactose favors actinomycin production in Streptomyces antibioticus over arabinose, xylose, glucose, fructose and rhamnose (26), while glycerol was the optimal carbon source for actinomycin production by S.…”

Section: Discussionmentioning

confidence: 99%

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New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

Machushynets

Aboutabl

et al. 2021

Preprint

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Streptomycetes are major producers of bioactive natural products, including the majority of the antibiotics. While much if the low-hanging fruit has been discovered, it is predited that less than 5% of the chemical space has been mined. Here, we describe the novel actinomycins L1 and L2, which are produced by Streptomyces sp. MBT27. The molecules were discovered via metabolic analysis combined with molecular networking of cultures grown with different combinations of carbon sources. Actinomycins L1 and L2 are diastereoisomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via a unique spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Feeding anthranilamide to cultures of Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27 but only produces actinomycin X2, resulted in the production of actinomycin L. This shows that actinomycin L results from joining two distinct metabolic pathways, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

Machushynets

Aboutabl

et al. 2021

Preprint

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“…The production of actinomycins by Streptomyces spp. is strongly influenced by the carbon source, whereby the preferred carbon source varies from strain to strain 45 – 49 . D-galactose favors actinomycin production in Streptomyces antibioticus over arabinose, xylose, glucose, fructose and rhamnose 45 , while glycerol was the optimal carbon source for actinomycin production by S. antibioticus Tü 6040 and S. antibioticus SR15.4 46 , 47 .…”

Section: Discussionmentioning

confidence: 99%

“…However, increasing the glucose concentration to 2% blocked the production of actinomycins. Glucose was previously reported to repress the transcription of the gene for hydroxykynureninase, which is involved in the formation of the main actinomycin precursor 4-MHA 45 . Importantly, in our experiments the carbon source not only promoted the overall production levels, but also contributed to the chemical diversity of the actinomycins, including the production of actinomycin L. This coincided with the production of anthranilamide, an essential substrate to form this novel actinomycin variant.…”

Section: Discussionmentioning

confidence: 99%

Discovery of actinomycin L, a new member of the actinomycin family of antibiotics

Machushynets

Aboutabl

et al. 2022

Sci Rep

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Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has been discovered, it is predicted that less than 5% of the chemical space of natural products has been mined. Here, we describe the discovery of the novel actinomycins L1 and L2 produced by Streptomyces sp. MBT27, via application of metabolic analysis and molecular networking. Actinomycins L1 and L2 are diastereomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Such a structural feature has not previously been identified in naturally occurring actinomycins. Adding anthranilamide to cultures of the actinomycin X2 producer Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27, resulted in the production of actinomycin L. This supports a biosynthetic pathway whereby actinomycin L is produced from two distinct metabolic routes, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.

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“…It was maintained and grown in the glutamatemineral salts medium supplemented with 1% galactose plus 0.1% glucose as described. 21 Incubation was at 30 C and 220 rpm in a New Brunswick G 25 shaker.…”

Section: Strains and Culturesmentioning

confidence: 99%

Biosynthetic rivalry of o-aminophenol-carboxylic acids initiates production of hemi-actinomycins in Streptomyces antibioticus

et al. 2014

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Actinomycins consist of two pentapeptide lactone rings attached to 2-amino-4,6-dimethyl-3-oxophenoxazine-1,9-dicarboxylic acid (actinocin). The actinocin moiety is formed through oxidative condensation of two 3-hydroxy-4-methylanthranilic acid (4-MHA) pentapeptide lactones (actinomycin halves) as the last step of actinomycin biosynthesis. We found that feeding of 4-MHA or its putative biogenetic precursor 3-hydroxyanthranilic acid (3-HA) to Streptomyces antibioticus induced formation of different new compounds at the expense of actinomycins. These contain only one pentapeptide lactone ring attached to the b-side of their phenoxazinone ring systems and are formed through premature condensation of the externally added abundant 4-MHA or 3-HA with actinomycin halves. They were termed hemi-actinomycins and C-demethyl-hemi-actinomycins, respectively, which differ from each other in the presence or absence of one or both methyl groups in their phenoxazinone moieties. 3-HA also induces synthesis of various C-demethylactinomycins formed through condensation of actinomycin halves in which 3-HA had been incorporated by the 4-MHA incorporating enzyme in lieu of 4-MHA. 3-HA was not converted to 4-MHA as revealed by its inability to stimulate synthesis of actinomycin or hemi-actinomycin synthesis and thus remained a substrate analogue of 4-MHA rather than its precursor.In contrast to S. antibioticus, actinomycin-producing streptomycetes such as Streptomyces chrysomallus or Streptomyces parvulus do not form hemi-structured actinomycins when fed with 3-HA or 4-MHA.They do not possess the enzyme phenoxazinone synthase (PHS) which in S. antibioticus is present and most probably catalyses premature condensation of abundant 4-MHA or 3-HA with actinomycin halves.Testing hemi-acinomycin IV for drug activity revealed that it intercalates into DNA and inhibits relaxation and supertwisting of DNA by topoisomerase I and DNA-gyrase like actinomycin IV (D). Moreover, it has inhibitory activity on growth of Bacillus subtilis.

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The Role of Nutrition in the Synthesis of Actinomycin

Cited by 56 publications

References 14 publications

New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

Discovery of actinomycin L, a new member of the actinomycin family of antibiotics

Biosynthetic rivalry of o-aminophenol-carboxylic acids initiates production of hemi-actinomycins in Streptomyces antibioticus

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