Actinomycin

Katz, Edward

doi:10.1007/978-3-642-46054-8_25

Cited by 15 publications

(1 citation statement)

References 165 publications

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“…For example: the influence of sarcosine on the synthesis of actinomycin X and of valine and leucine on the synthesis of aurantin (actinomycin C) was most effective at their introduction before the beginning of antibiotic synthesis or right after it (2,3,4). In this case the growth of actinomycin producers Streptomyces antibioticus (5) and Actinomyces sp. N2 (3) and antibiotic synthesis (accordingly for actinomycin X and aurantin) flew as a typical trophophasa -idiophasa fermentation.…”

Section: Resultsmentioning

confidence: 99%

Influence of the Amino Acid DL-Histidine on the Biosynthesis of Antibiotic 695, Produced by StrainStreptomyces Galbus(F) Subsp.Achromogenes695

Yocheva¹,

Antonova-Nikolova²

2001

Biotechnology & Biotechnological Equipment

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Section: Resultsmentioning

confidence: 99%

Influence of the Amino Acid DL-Histidine on the Biosynthesis of Antibiotic 695, Produced by StrainStreptomyces Galbus(F) Subsp.Achromogenes695

Yocheva¹,

Antonova-Nikolova²

2001

Biotechnology & Biotechnological Equipment

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Aromatic C-Methyltransferases with Antipodal Stereoselectivity for Structurally Diverse Phenolic Amino Acids Catalyze the Methylation Step in the Biosynthesis of the Actinomycin Chromophore

Crnovčić

Süssmuth²,

Keller

2010

Biochemistry

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The actinomycin biosynthetic gene cluster of Streptomyces chrysomallus harbors two paralogous genes, acmI and acmL, encoding methyltransferases. To unveil their suspected role in the formation of 3-hydroxy-4-methyl-anthranilic acid (4-MHA), the building block of the actinomycin chromophore, each gene was expressed in Escherichia coli. Testing the resulting ∼40 kDa His(6)-tagged proteins with compounds of biogenetic relevance as substrates and S-adenosyl-l-methionine revealed that each exclusively methylated 3-hydroxykynurenine (3-HK) with formation of 3-hydroxy-4-methylkynurenine (4-MHK) identified by its in vitro conversion to 4-MHA with hydroxykynureninase. AcmI and AcmL methylate also hydroxyphenyl-amino propanoic acids such as p-tyrosine, m-tyrosine, or 3,4-dihydroxy-l-phenylalanine (DOPA) but at a lower rate than 3-HK. The presence of the α-amino group was necessary for substrate recognition. Phenolic acids with shorter chains such as 4-hydoxyphenyl-l-glycine (HPG), 3-hydroxybenzoic acid (3-HB), or 3-hydroxyanthranilic acid (3-HA) gave no product. Both enzymes were stereospecific for the optical configuration at α-C with unprecedented antipodal selectivity for the d-enantiomer of 3-HK and the l-enantiomer of p-tyrosine or m-tyrosine. AcmI and AcmL show sequence similarity to various C- and O-methyltransferases from bacteria. Phylogenetic analysis places them into the clade of C-methyltransferases comprising among others orthologues involved in 4-MHA formation of other biosynthesis systems and methyltransferases putatively involved in the C-methylation of tyrosine. Remarkably, computational remodelling of AcmI and AcmL structures revealed significant similarity with the 3-D structures of type 1 O-methyltransferases from plants such as caffeic acid O-methyltransferase (COMT) and other phenylpropanoid methyltransferases. The relevance of 3-HK or 3-HA methylation in the actinomycin biosynthesis pathways of different actinomycetes is discussed.

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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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Actinomycin

Cited by 15 publications

References 165 publications

Influence of the Amino Acid DL-Histidine on the Biosynthesis of Antibiotic 695, Produced by StrainStreptomyces Galbus(F) Subsp.Achromogenes695

Influence of the Amino Acid DL-Histidine on the Biosynthesis of Antibiotic 695, Produced by StrainStreptomyces Galbus(F) Subsp.Achromogenes695

Aromatic C-Methyltransferases with Antipodal Stereoselectivity for Structurally Diverse Phenolic Amino Acids Catalyze the Methylation Step in the Biosynthesis of the Actinomycin Chromophore

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

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