Maggiemycin and anhydromaggiemycin: Two novel anthracyclinone antitumor antibiotics. Isolation, structures, partical synthesis and biological properties.

Pandey, Ramesh C.; Toussaint, Margaret W.; McGuire, Jeffrey C.; Thomas, M. C.

doi:10.7164/antibiotics.42.1567

Cited by 26 publications

(14 citation statements)

References 8 publications

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“…Aklaviketone, which is 11-deoxymaggiemycin, was proposed to be an intermediate in the formation of aklavinone . Our dauE mutant strain, SC5-24, accumulates maggiemycin and is therefore similar to the previously described maggiemycin-accumulating strain, A21 (McGuire et al, 1980a;Pandey et al, 1989). According to the hypothesis proposed by , maggiemycin-accumulating strains are deficient in their ability to convert aklaviketone to aklavinone, the normal 1 1-hydroxylase substrate.…”

Section: Discussionsupporting

confidence: 88%

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Biosynthesis of anthracydines: enzymic conversion of aklanonic acid to aklavinone and -rhodomycinone by anthracycline-producing streptomycetes

Connors

Bartel

Strohl

1990

Journal of General Microbiology

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Aklanonic acid, a substituted anthraquinone, is the earliest stable intermediate isolated so far in the biosynthesis of anthracycline antibiotics. Desalted, soluble cell extracts of Streptomyces sp. C5 and Streptomyces peucetius (ATCC 29050) converted aklanonic acid to E-rhodomycinone in an S-adenosyl-L-methionine-and NADPHdependent sequence of reactions. Aklanonic acid was methylated to form aklanonic acid methyl ester (AAME), which was cyclized to form aklaviketone. Aklaviketone was reduced to aklavinone by an NADPH-linked reductase. When extracts of Streptomyces sp. C5 and S. peucetius were used, aklavinone was hydroxylated at C-11 by an NADPH-and oxygen-dependent reaction to form E-rhodomycinone. Cell extracts of Streptomyces galilaeus strains ATCC 31133 and 31671 converted aklanonic acid to aklavinone in the same manner, but neither of the S. gdilaeus strains hydroxylated aklavinone to E-rhodomycinone. Mutants of Streptomyces sp. C5 blocked at steps in the conversion of aklanonic acid to aklavinone, and which accumulated aklanonic acid (SC5-39; duuC), AAME (SC5-138; duuD, duuE), and aklaviketone (SO-159; duuE, duuF), lacked the expected enzymic activities. In a mutant (SC5-24; duuE) lacking aklaviketone reductase, but retaining aklavinone 11-hydroxylase activity, maggiemycin was formed as an apparent shunt product. An enzymic pathway for 8-rhodomycinone and maggiemycin formation is consistent with the data presented.

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Section: Discussionsupporting

confidence: 88%

“…C5. The complete description of maggiemycin has recently been published by Pandey et al (1989). Similarly, isolated the brown-red 7-0x0 anthracyclinone, aklaviketone, from cultures of a mutant of S .…”

Section: Discussionmentioning

confidence: 99%

Biosynthesis of anthracydines: enzymic conversion of aklanonic acid to aklavinone and -rhodomycinone by anthracycline-producing streptomycetes

Connors

Bartel

Strohl

1990

Journal of General Microbiology

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“…Mutants of Streptomyces sp. strain C5 in which aklaviketone reductase activity is blocked (dauE mutants) accumulate the purple-pigmented compound maggiemycin (25), which is produced as a shunt product of aklaviketone hydroxylated at C-11 (3,6,10).…”

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confidence: 99%

Cloning, sequencing, and analysis of aklaviketone reductase from Streptomyces sp. strain C5

Dickens

Strohl

1996

J Bacteriol

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DNA sequence analysis of a region of the Streptomyces sp. strain C5 daunomycin biosynthesis gene cluster, located just upstream of the daunomycin polyketide biosynthesis genes, revealed the presence of six complete genes. The two genes reading right to left include genes encoding the potentially translationally coupled gene products, an acyl carrier protein and a ketoreductase, and the four genes reading divergently, left to right, include two open reading frames of unknown function followed by a gene encoding an apparent glycosyltransferase and dauE, encoding aklaviketone reductase. Extracts of Streptomyces lividans TK24 containing recombinant DauE catalyzed the NADPH-specific conversion of aklaviketone, maggiemycin, and 7-oxodaunomycinone to aklavinone, -rhodomycinone, and daunomycinone, respectively. Neither the product of dauB nor that of the ketoreductase gene directly downstream of the acyl carrier protein gene demonstrated aklaviketone reductase activity.

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“…Decreased RHO accumulation in the dnrH mutant could possibly result from a decrease in dnrE expression, because, on the basis of the recent work of Dickens et al (10), dnrE must encode the 7-ketoreductase required for the conversion of aklaviketone to RHO. Lack of this enzyme would result in the formation of maggiemycin, a purple shunt product of the DNR pathway (32). Since the insertional inactivation of dnrH might have affected expression of the dnrE gene immediately downstream, a 1.1-kb BsaAI-AvrII segment containing dnrE was cloned in pWHM3, and the resulting plasmid was introduced into the WMH1708 strain to determine the effect on RHO and DNR production.…”

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confidence: 99%

Enhanced antibiotic production by manipulation of the Streptomyces peucetius dnrH and dnmT genes involved in doxorubicin (adriamycin) biosynthesis

Scotti

Hutchinson

1996

J Bacteriol

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Sequence analysis of a 3.4-kb region Streptomyces peucetius daunorubicin (DNR) gene cluster established the presence of the dnrH and dnmT genes. In dnrH mutants, DNR production increased 8.5-fold, compared with that in the wild-type strain, while dnmT mutants accumulated -rhodomycinone (RHO), which normally becomes glycosylated in daunorubicin biosynthesis. Hence, dnmT may be involved in the biosynthesis or attachment of daunosamine to RHO or in the regulation of this process. Since the DnrH protein is similar to known glycosyl transferases, this protein may catalyze the conversion of DNR to its polyglycosylated forms, known as baumycins. Overexpression of dnmT in the wild-type and dnrH mutant strains resulted in a major decrease in RHO accumulation and increase in DNR production.Daunorubicin (DNR) and its C-14 hydroxylated derivative doxorubicin (DXR) are important antitumor anthracycline antibiotics (26) isolated from Streptomyces peucetius ATCC 29050 (2, 5, 7). Studies of DNR and DXR production ( Fig. 1) in this organism have elucidated the organization and regulation of many of the biosynthetic genes (11,12,21,23,29,31), as well as the mechanism of antibiotic resistance (14, 19) and the regulation of DNR and DXR biosynthesis (20,28,34).Here we report the characterization of the dnrH and dnmT genes, which are situated between the dpsH (formerly dnr-ORF7) and dnrE (formerly dnrH) genes in the cluster of DXR biosynthesis genes ( Fig. 2 and 3). Dickens et al. (10) have described homologs of these genes in the Streptomyces sp. strain C5 (dau-ORF2 and -ORF3) but were only able to suggest a possible function for dnrH, as deduced from the DNA sequence. From the results of the expression of the dnrH and dnmT genes in the wild type and a dnrH mutant strain, plus the effects of insertional inactivation of both genes, it seems likely that these two genes govern steps subsequent to the formation of the aglycone ε-rhodomycinone (RHO), a key intermediate of DNR biosynthesis (Fig. 1). Moreover, introduction of dnmT on a high-copy-number plasmid into the dnrH mutant resulted in an 8.5-fold increase in DNR production with a concomitant large decrease in the level of RHO, a useless by product of DNR-producing strains.Sequence analysis of the dnrH and dnmT genes. DNA sequencing of both strands of a 2,162-nucleotide (nt) SphIBamHI fragment by previously reported methods (29) followed by CODONPREFERENCE analysis (9) revealed the C-terminal end of dpsH (the rest of this gene has been sequenced in other work [30]), the complete dnmT gene, and the N-terminal part of dnrH. The remainder of dnrH extends 931 nt into the adjacent 1.3-kb BamHI-AlwNI fragment described by Grimm et al. (13) (Fig. 3). The first ATG codon for dnmT is likely to be located at nt 237 (Fig. 3), even though a probable ribosome binding site is not evident near the 5Ј end of this open reading frame (ORF), and a stop codon (TGA) is located at position 1,752, which suggests that dnmT encodes a 505-amino-acid polypeptide with an M r of 55,433. The dnrH gene has a pr...

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Maggiemycin and anhydromaggiemycin: Two novel anthracyclinone antitumor antibiotics. Isolation, structures, partical synthesis and biological properties.

Cited by 26 publications

References 8 publications

Biosynthesis of anthracydines: enzymic conversion of aklanonic acid to aklavinone and -rhodomycinone by anthracycline-producing streptomycetes

Biosynthesis of anthracydines: enzymic conversion of aklanonic acid to aklavinone and -rhodomycinone by anthracycline-producing streptomycetes

Cloning, sequencing, and analysis of aklaviketone reductase from Streptomyces sp. strain C5

Enhanced antibiotic production by manipulation of the Streptomyces peucetius dnrH and dnmT genes involved in doxorubicin (adriamycin) biosynthesis

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