Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of Streptomyces. In contrast, only one known non-wild type species, Streptomyces peucetius subspecies caesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin. His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. This is of more than academic interest because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum. More efficient production techniques have brought the price down to $1.1 million per kg for the non-liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.
In molecular biology, the polyketide synthesis cyclase family of proteins includes a number of cyclases involved in polyketide synthesis in a number of actinobacterial species.
Streptomyces bikiniensis is a bacterium species from the genus Streptomyces which has isolated from soil from the island Bikini atoll. Streptomyces bikiniensis produces streptomycin II and carboxypeptidase.
Streptomyces cellulosae is a bacterium species from the genus of Streptomyces which has been isolated from garden soil. Streptomyces cellulosae produces fungichromin.
Streptomyces chromofuscus is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces chromofuscus produces phospholipase D, herboxidiene, pentalenolactone O and carazostatins.
Streptomyces galbus is a bacterium species from the genus of Streptomyces which has been isolated from soil from West Bengal. Streptomyces galbus produces xylanase, galbonolides A, galbonolides B and the actinomycin X complex.
Streptomyces actuosus is a bacterium species from the genus of Streptomyces. Streptomyces actuosus produces nosiheptide and staurosporin.
Streptomyces halstedii is a bacterium species from the genus of Streptomyces which has been isolated from deeper soil layers. Streptomyces halstedii produces magnamycin B, vicenistatin deltamycin A2, deltamycin A3, bafilomycin B1 and bafilomycin C1. Streptomyces halstedii also produces complex antifungal antibiotics like oligomycins and the antibiotics anisomycin and sinefungin.
Streptomyces ipomoeae is a bacterium species from the genus of Streptomyces which has been isolated from rot from potatoes. Streptomyces ipomoeae produces thaxtomin C and ipomycin. Streptomyces ipomoeae can cause soft rot disease on sweet potatoes.
Streptomyces olivaceoviridis is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces olivaceoviridis produces chitinase and xylanase.
Streptomyces phaeochromogenes is a bacterium species from the genus of Streptomyces. Streptomyces phaeochromogenes produces tyrosinate, bromoperoxidase, ditryptophenalin, phaeochromycin A, phaeochromycin B, phaeochromycin C, phaeochromycin D and phaeochromycin E. Streptomyces phaeochromogenes also produces moenomycin and bambermycin.
Streptomyces platensis is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces platensis produces oxytetracycline, platensimycin, migrastatin, isomigrastatin, platencin, dorrigocin A, dorrigocin B and terramycine.
Streptomyces pulveraceus is a bacterium species from the genus of Streptomyces which has been isolated from soil in Fukuchiyama in Japan. Streptomyces pulveraceus produces zygomycine and fostriecin.
Streptomyces resistomycificus is a bacterium species from the genus of Streptomyces which has been isolated from soil. Streptomyces resistomycificus produces the pentacyclic polyketide resistomycin.
Streptomyces rochei is a bacterium species from the genus of Streptomyces which has been isolated from soil in Russia. Streptomyces rochei produces borrelidin, butyrolactol A, butyrolactol B, uricase and streptothricin. Streptomyces rochei has antifungal activity against Fusarium oxysporum f.sp. lycopersici and Aspergillus fumigatus. Streptomyces rochei produces moenomycin and bambermycin. Streptomyces rochei produces amicetin A, amicetin B, amicetin C and streptolin. Streptomyces rochei produces endo-β-N-acetylglucosaminidase mithramycin, amicetin, bamicetin, and plicacetin.
Streptomyces spiroverticillatus is a bacterium species from the genus of Streptomyces which has been isolated from soil in Japan. Streptomyces spiroverticillatus produces tautomycin.
Streptomyces tendae is a bacterium species from the genus of Streptomyces which has been isolated from soil in France. Streptomyces tendae produces carbomycin, streptofactin, geosmin, cervimycin A-D and nikkomycins. Also said to be the source of Tendamistat, an alpha amylase inhibitor.
Streptomyces viridosporus is a bacterium species from the genus of Streptomyces. Streptomyces viridosporus produces sistomycine and lignin peroxidase. Streptomyces viridosporus can degrade lignin and humic acids. Streptomyces viridosporus also produces moenomycin A, a component of bambermycin.
Tetracenomycin C is an antitumor anthracycline-like antibiotic produced by Streptomyces glaucescens GLA.0. The pale-yellow antibiotic is active against some gram-positive bacteria, especially against streptomycetes. Gram-negative bacteria and fungi are not inhibited. In considering the differences of biological activity and the functional groups of the molecule, tetracenomycin C is not a member of the tetracycline or anthracyclinone group of antibiotics. Tetracenomycin C is notable for its broad activity against actinomycetes. As in other anthracycline antibiotics, the framework is synthesized by a polyketide synthase and subsequently modified by other enzymes.
Prescopranone is a key intermediate in the biosynthesis of scopranones. Prescopranone is the precursor to scopranone A, scopranone B, and scopranone C, which are produced by Streptomyces sp. BYK-11038.
