Disease relevance of Tetracenomycin

• Selective expression of different combinations of the Streptomyces glaucescens tetracenomycin (Tcm) tcmJKLMN genes in a tcmGHIJKLMNO null background has been used to show that the Tcm PKS consists of at least the TcmKLMN proteins [1].
• RESULTS: We demonstrate that E. coli holo-ACP synthase (ACPS), a fatty acid biosynthesis enzyme, can catalyze P-pant transfer in vitro to the Streptomyces PKS ACPs required for the biosynthesis of the polyketide antibiotics granaticin, frenolicin, oxytetracycline and tetracenomycin [2].
• Actinobolin, atropine, carrageenan, megalomycin C, suramin, and tetracenomycin C were tested for their activity against African swine fever virus replication [3].
• Although similar in structure to tetracenomycin C, which is an antibiotic against Gram-positive bacteria, 5838-DNI has different antibacterial activity [4].
• Actinobolin, amicetin and tetracenomycin C were also active against viruses other than herpes simplex [5].

High impact information on Tetracenomycin

• Cloning and heterologous expression of a gene cluster for the biosynthesis of tetracenomycin C, the anthracycline antitumor antibiotic of Streptomyces glaucescens [6].
• The tcm biosynthetic and resistance genes occur as a single cluster in the S. glaucescens genome and are expressed in heterologous streptomycete hosts like S. lividans, resulting in the overproduction of pigmented intermediates of the tetracenomycin C biosynthetic pathway [6].
• Through complementation of mutations specifically blocking the biosynthesis of tetracenomycin C by Streptomyces glaucescens and selecting for resistance to tetracenomycin C in Streptomyces lividans, all of the genes for the production of tetracenomycin C were inserted in pIJ702, a high copy-number Streptomyces gene cloning vector [6].
• Tetracenomycin F2 cyclase (tcmI gene product), catalyzes an aromatic rearrangement in the biosynthetic pathway for tetracenomycin C in Streptomyces glaucescens [7].
• Unexpectedly, however, when the C-terminal domain of the gris ARO/CYC was expressed in a context where aromatase activity was absent, it could modulate the chain length specificity of the tetracenomycin (tcm) minimal PKS, leading to the formation of a novel 18-carbon product in addition to the expected 20-carbon one [8].

Chemical compound and disease context of Tetracenomycin

• BACKGROUND: Elloramycin is an anthracycline-like antitumor drug related to tetracenomycin C which is produced by Streptomyces olivaceus Tü2353 [9].
• Tetracenomycin F1 monooxygenase: oxidation of a naphthacenone to a naphthacenequinone in the biosynthesis of tetracenomycin C in Streptomyces glaucescens [10].

Biological context of Tetracenomycin

• Nucleotide sequence analysis of the tcmG gene has suggested that the TcmG protein is responsible for the triple-hydroxylation of tetracenomycin (Tcm) A2 to Tcm C in Streptomyces glaucescens (Decker, H., Motamedi, H., and Hutchinson, C.R. (1993) J. Bacteriol. 175, 3876-3886) [11].
• Triple hydroxylation of tetracenomycin A2 to tetracenomycin C in Streptomyces glaucescens. Overexpression of the tcmG gene in Streptomyces lividans and characterization of the tetracenomycin A2 oxygenase [11].
• The nascent polyketide backbone must undergo a series of regiospecific cyclizations to form a tetracenomycin-like tetracyclic intermediate [12].
• RESULTS: The expression of cosmid 16F4 in several producers of glycosylated antibiotics has been shown to produce tetracenomycin derivatives containing different 6-deoxysugars [9].
• Certain mutations in the tcmVI region of the Streptomyces glaucescens chromosome affect formation of the D ring of the polyketide antibiotic tetracenomycin C (TCM C) [13].

Gene context of Tetracenomycin

• Incubations of tetracenomycin ACP (TcmM) with the Escherichia coli FAS ACP (AcpP) unexpectedly revealed that, in addition to the self-malonylation process, TcmM can catalyze the malonylation of AcpP [14].
• In the absence of alternative acyl donors, ZhuC severely retarded the activity of the tcm minimal PKS [15].
• The acyl carrier protein (ACP) of the tetracenomycin C polyketide synthase, encoded by the tcmM gene, has been expressed in both Streptomyces glaucescens and Escherichia coli and purified to homogeneity [16].
• Sequence and transcriptional analysis of the Streptomyces glaucescens tcmAR tetracenomycin C resistance and repressor gene loci [17].
• The five ORFs show high sequence similarities to ORFs that were previously identified in the granaticin, actinorhodin, tetracenomycin and whiE PKS gene clusters [18].

Analytical, diagnostic and therapeutic context of Tetracenomycin

• Key information about the biosynthesis of polyketide metabolites has been uncovered by sequence analysis of the tetracenomycin C polyketide synthase genes (tcml) from Streptomyces glaucescens GLA [19].
• Crystallization and preliminary X-ray analysis of tetracenomycin A2 oxygenase: a flavoprotein hydroxylase involved in polyketide biosynthesis [20].

References