Actinorhodin

From the cultures of streptomycetes were isolated anthacyclinones like aklavi-none. Various aromatic polyketide antibiotics produced by fungi and bacteria have quinoid structures, for example, doxorubicin, rhodomycin, and actinorhodin. ... 

Figure 11.1 Representative secondary metabolites produced by Streptomyces ceolicolor and other microorganisms, including aromatic polyketides actinorhodin and tetrohydroxynaphthalene (a), side-rophore desferrioxamines (b), polyunsaturated fatty acid eicosapentaenoic acid (c) and terpenoids beta-...

Kendrew, S.G., Hopwood, D.A. and Marsh, E.N.G. (1997) Identification of a monooxygenase from Streptomyces coelicolor A3(2) involved in biosynthesis of actinorhodin purification and characterization of the recombinant enzyme. Journal of Bacteriology, 179, 4305—4310. 

Figure 12.5 A. Comparison of the CHS monomer (left) and P-ketoacyl synthase monomer (right). The structurally conserved secondary structure of each monomer s upper domain is colored in blue (a-helix) and gold (P-strand). Portions of each protein monomer forming the dimer interface are colored purple. The side-chains of the catalytic residues of CHS (Cysl64, His303, Asn336) and P-ketoacyl synthase (Cysl63, His303, His340) are shown. B. Sequence conservation of the catalytic residues of CHS, 2-PS, p-ketoacyl synthase (FAS II), and the ketosynthase modules of 6-deoxyerythronolide B synthase (DEBS), actinorhodin synthase (ActI) and tetracenomycin synthase (TcmK). The catalytic residues are in red.

Sciara G, Kendrew SG, Miele AE, Marsh NG, Federici L, et al. 2003. The structure of ActVA-Orf6, a novel type of monooxygenase involved in actinorhodin biosynthesis. EMBO J 22 205-215. 

Uguru GC, Stephens KE, Stead JA, Towle JE, Baumberg S, McDowall KJ. (2005) Transcriptional activation of the pathway-specific regulator of the actinorhodin biosynthetic genes in Streptomyces coelicolor. Mol Microbiol 58 131-150. 

The ribosome-associated ppGpp synthetase (RelA) is required for antibiotic production under the conditions of nitrogen limitation in S. coelicolor A3 and for cephamycin C production in S. clavuligerus. Deletion of the relA in S. coelicolor A3 results in the loss of production of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red) and... 

Kim E-S, Hong H-J, Choi C-Y, Cohen SN, Modulation of actinorhodin biosynthesis in Streptomyces lividans by glucose repression of afsR2 gene transcription,... 

The aromatization often takes place after linear precursors have been modified as in the biosynthesis of actinorhodin, where condensation followed by ketone reduction takes place before aromatization (Scheme 7.7) [31]. 

A 26-kb gene cluster encoding enzymes for synthesis of the blue antibiotic actinorhodin by Streptomyces coelicolor has been cloned and sequenced.332337 The three large 10-kb genes required for formation of the broad-spectrum antibiotic erythromycin by Saccharopolyspora erythraea have also been cloned and sequenced.337 339 In both cases, the genes... 

A. Actinorhodin, Tetracenomycin, Doxorubicin, and Other Bacterial Aromatic Polyketide Synthases... 

Figure 3 Aromatic PKS gene clusters and actinorhodin biosynthesis. Partial gene clusters for the polyketides actinorhodin (act), tetracenomycin (tcm), and doxorubicin (dps) are shown. Reconstitution of combinations of act genes in a PKS clean host have led to a proposed pathway by which the early stages of actinorhodin biosynthesis occur.

Figure 10 Examples of unnatural aromatic polyketides. Libraries of aromatic poly-ketides have been generated using combinations from the actinorhodin, tetracenomycin, frenolicin, griseusin, and whiE spore pigment gene clusters.

MA Fernandez-Moreno, E Martinez, L Boto, DA Hopwood, F Malpartida. Nucleotide sequence and deduced functions of a set of cotranscribed genes of Streptomyces coelicolor A3(2) including the polyketide synthase for the antibiotic actinorhodin. J Biol Chem 267 19278-19290, 1992. 

J Dreier, AN Shah, C Khosla. Kinetic analysis of the actinorhodin aromatic polyketide synthase. J Biol Chem 274 25108-25112, 1999. 

PL Bartel, CB Zhu, JS Lampel, DC Dosch, NC Conners, WR Strohl, JM Beale, HG Floss. Biosynthesis of anthraquinones by interspecies cloning of actinorhodin biosynthesis genes in Streptomyces. clarification of actinorhodin gene functions. J Bacteriol 172 4816-4826, 1990. 

In similar experiments, cell-free preparations of a Streptomyces coelicolor strain containing the minimal PKS involved in actinorhodin biosynthesis were shown to produce compounds called SEK4 and SEK4b, molecules generated as shunt products of the normal pathway (Fig. 7). When the strain also included genes for the KR, ARO, and CYC activities, a more elaborate structure, 3,8-dihydroxy-l-methylanthraquinone-2-carboxylic acid (DMAC), was obtained (Fig. 7) [8], Biosynthesis of SEK4 and SEK4b has also been accomplished in... 

Figure 7 Cell-free biosynthesis of SEK4, SEK4b, and DMAC. A strain of Streptomyces coelicolor in which the actinorhodin-minimal PKS genes had been overexpressed, produced both SEK4 and SEK4b. Expression of the KR, ARO, and CYC genes in addition to the minimal PKS resulted in the biosynthesis of DMAC. Synthesis of SEK4 and SEK4b has also been achieved using purified proteins in vitro.

CW Carreras, R Pieper, C Khosla. Efficient synthesis of aromatic polyketides in vitro by the actinorhodin polyketide synthase. J Am Chem Soc 118 5158-5159, 1996. 

MP Crump, J Crosby, CE Dempsey, M Murray, DA Hopwood, TJ Simpson. Conserved secondary structure in the actinorhodin polyketide synthase acyl carrier pro-... 

A-L Matharu, RJ Cox, J Crosby, KJ Byrom, TJ Simpson. MCAT is not required for in vitro polyketide synthesis in a minimal actinorhodin polyketide synthase from Streptomyces coelicolor. Chem Biol 5 699-712, 1998. 

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