Biosynthesis of Actinorhodin and Related Antibiotics: Discovery of Alternative Routes for Quinone Formation Encoded in the act Gene Cluster

Okamoto, Susumu; Taguchi, Tanezo; Ochi, Kozo; Ichinose, Koji

doi:10.1016/j.chembiol.2009.01.015

Cited by 75 publications

(77 citation statements)

References 35 publications

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“…Actinorhodin (ACT) is a red/blue pH-indicating benzoisochromanequinone made by a type II polyketide synthase-based pathway involving a 22-gene cluster (291). Undecylprodiginines (REDs) are red hydrophobic tripyrroles made by a fatty acid synthase-like pathway involving a 22-gene cluster (292).…”

Section: Control Of Five Extensively Studied S Coelicolor Antibioticmentioning

confidence: 99%

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Liu

Chater

Chandra

et al. 2013

Microbiol Mol Biol Rev

578

536

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SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor , the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.

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Section: Control Of Five Extensively Studied S Coelicolor Antibioticmentioning

confidence: 99%

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Liu

Chater

Chandra

et al. 2013

Microbiol Mol Biol Rev

578

536

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“…3 (m/z 268) was extensively activated. The metabolites with m/z of 631, 633, and 649 were assigned as ␥-actinorhodin, ␥=-actinorhodin, and ε-actinorhodin, respectively (26,32,33), while the metabolite with m/z 647 was considered a novel actinorhodinrelated compound, because disruption of actII-ORF4 in KO-1130 resulted in almost complete abolition of these four metabolites simultaneously (see Fig. S5A in the supplemental material).…”

Section: Isolation and Characterization Of Rifampin-resistant Mutantsmentioning

confidence: 99%

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Tanaka

Kasahara²,

Hirose³

et al. 2013

J Bacteriol

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A subset of rifampin resistance (rpoB) mutations result in the overproduction of antibiotics in various actinomycetes, including Streptomyces, Saccharopolyspora, and Amycolatopsis, with H437Y and H437R rpoB mutations effective most frequently. Moreover, the rpoB mutations markedly activate (up to 70-fold at the transcriptional level) the cryptic/silent secondary metabolite biosynthetic gene clusters of these actinomycetes, which are not activated under general stressful conditions, with the exception of treatment with rare earth elements. Analysis of the metabolite profile demonstrated that the rpoB mutants produced many metabolites, which were not detected in the wild-type strains. This approach utilizing rifampin resistance mutations is characterized by its feasibility and potential scalability to high-throughput studies and would be useful to activate and to enhance the yields of metabolites for discovery and biochemical characterization. Actinomycetes produce a variety of natural products that are of major importance in the pharmaceutical industry. More than 50% of all anti-infective and anticancer compounds developed over the past 25 years have been natural products or derivatives thereof (1). Discovery of novel antibiotics and strain improvement for overproduction are important in applied microbiology research, especially in the production of clinically important antibiotics as well as antibiotics important in veterinary medicine and agriculture. There is accumulating evidence that the ability of actinomycetes to produce antibiotics and other bioactive secondary metabolites has been underestimated due to the presence of cryptic gene clusters. That is, genome sequencing projects have revealed many biosynthetic gene clusters for the production of unknown secondary metabolites. For example, Streptomyces coelicolor, Streptomyces avermitilis, Streptomyces griseus, and Saccharopolyspora erythraea are each known to produce three to five secondary metabolites but actually possess Ͼ20 clusters that encode known or predicted biosynthetic pathways for secondary metabolites (2-5). Exploitation of such genetic potential in actinomycetes may lead to the isolation of new biologically active compounds (6-8). We recently described a new method to increase antibiotic production in bacteria by modulating ribosomal components (ribosomal proteins or rRNA), i.e., by introducing mutations conferring drug resistance, as many antibiotics target the ribosome (9-11). This new approach, called "ribosome engineering" (12, 13), has several advantages, including the ability to screen for drug resistance mutations by simple selection on drugcontaining plates, even if the mutation frequency is extremely low (e.g., Ͻ10 Ϫ10 ), and the ability to select for mutations without prior genetic information. Hence, this method requires no induced mutagenesis. Interestingly, the introduction of several drug resistance mutations has a cumulative effect on antibiotic production (14-16).In addition to enhancement of antibiotic production, we have demon...

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“…Therefore, we turned our attention to ACT (Fig. 1A), a low-molecular mass organic compound that is the most well-known pigment produced by S. coelicolor A3(2) (19)(20)(21)(22)(23). We purified a large amount of ACT (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Many studies of its biosynthesis have been reported (20)(21)(22)(23); however, there have been only a few reports on its antibacterial activity (27), and its mechanism of action remains unknown. Some L-amino acid oxidases, which catalyze oxidation reactions in which H 2 O 2 is among the products, have been reported to show antibacterial activity (25,26).…”

Section: Discussionmentioning

confidence: 99%

Natural low-molecular mass organic compounds with oxidase activity as organocatalysts

Nishiyama

Hashimoto

Kusakabe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Organocatalysts, low-molecular mass organic compounds composed of nonmetallic elements, are often used in organic synthesis, but there have been no reports of organocatalysts of biological origin that function in vivo. Here, we report that actinorhodin (ACT), a natural product derived from Streptomyces coelicolor A3(2), acts as a biocatalyst. We purified ACT and assayed its catalytic activity in the oxidation of L-ascorbic acid and L-cysteine as substrates by analytical methods for enzymes. Our findings were as follows: (i) oxidation reactions producing H 2 O 2 proceeded upon addition of ACT to the reaction mixture; (ii) ACT was not consumed during the reactions; and (iii) a small amount (catalytic amount) of ACT consumed an excess amount of the substrates. Even at room temperature, atmospheric pressure, and neutral pH, ACT showed catalytic activity in aqueous solution, and ACT exhibited substrate specificity in the oxidation reactions. These findings reveal ACT to be an organocatalyst. ACT is known to show antibiotic activity, but its mechanism of action remains unknown. On the basis of our results, we propose that ACT kills bacteria by catalyzing the production of toxic levels of H 2 O 2 . We also screened various other natural products of bacterial, plant, and animal origins and found that several of the compounds exhibited catalytic activity, suggesting that living organisms produce and use these compounds as biocatalysts in nature.A catalyst is a substance that increases the rate of a chemical reaction but is not consumed in the reaction. Catalysts are classified as homogeneous or heterogeneous, and most of the major homogeneous catalysts are metal-containing catalysts. In general, enzymes and ribozymes, which are classified as homogeneous catalysts, are referred to as biocatalysts. Enzymes are large proteins that catalyze numerous reactions in living organisms whereas ribozymes are composed of RNA and are known to catalyze phosphoryl transfer reactions (involved in RNA selfsplicing), the formation of peptide bonds, and various other reactions (1-5). Organocatalysts, which are homogeneous catalysts, are low-molecular mass organic compounds derived from nonmetallic elements (e.g., carbon, oxygen, hydrogen, and nitrogen) (6). Organocatalysts are used in industry because they have the following advantages over metal-containing catalysts (7-10): (i) Organocatalysts exhibit catalytic activity under mild conditions (atmospheric pressure, room temperature, and neutral pH); (ii) disposal of depleted organocatalysts is inexpensive; (iii) environmental loads due to waste reaction mixtures containing organocatalysts are low; and (iv) the risk of product contamination by metal ions is low. Therefore, organocatalysts have been receiving much attention in the field of green chemistry (11).In our laboratory, we have been studying the metabolism of actinomycetes from both fundamental and applied points of view (12)(13)(14)(15). From Streptomyces, we discovered a previously unidentified enzyme, L-glutamate oxidase (EC 1.4.3...

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Biosynthesis of Actinorhodin and Related Antibiotics: Discovery of Alternative Routes for Quinone Formation Encoded in the act Gene Cluster

Cited by 75 publications

References 35 publications

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Activation and Products of the Cryptic Secondary Metabolite Biosynthetic Gene Clusters by Rifampin Resistance ( rpoB ) Mutations in Actinomycetes

Natural low-molecular mass organic compounds with oxidase activity as organocatalysts

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