Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1994-08-25
1997-03-25
Wax, Robert A.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
4353201, C07H 2104
Patent
active
056146191
DESCRIPTION:
BRIEF SUMMARY
The invention concerns secondary-metabolite biosynthesis genes from actinomycetes, a method of isolating secondary-metabolite and, in particular, 6-deoxy-sugar biosynthesis genes, from actinomycetes using the gene probes strD, strE, strL and strM gene probes from Streptomyces griseus DSM40236, and structurally related genes, as gene probes for detecting the genes snoT (coding for amphotheronolide B-dTDP-D-mycosaminyl transferase), snoD (coding for dTDP-D-glucose synthase) and snoM (coding for dTDP-4-keto-6-deoxy-D-glucose isomerase), or one or more secondary-metabolite biosynthesis genes from actinomycetes. The invention also concerns the use of secondary-metabolite biosynthesis genes thus isolated.
One of the fields of activity in recombinant DNA technology is the isolation of particular genes directly out of the genome. In order to detect the gene to be isolated, gene probes can, for example, be employed which bind specifically to the desired DNA sequence. In this way, this latter sequence can be "fished out" (detected by screening) from a large number of other sequences.
Secondary-metabolite biosynthesis genes (genes for antibiotics, anthelmintics, antifungal substances, enzyme inhibitors, dyes, etc.) which have hitherto been investigated are present adjacent to each other within a unit on the bacterial chromosome or on very large plasmids. This applies particularly to streptomycetes and other actinomycetes [C. L. Hershberger et al. (1989), Genetics and Molecular Biology of Industrial Microorganisms, Am. Soc. for Microbiol., Washington, D.C. 20005, pp. 35-39, p. 58, pp. 61-67, pp. 147-155].
Thus, in actinomycetes, genes for the biosynthesis of 6-deoxy sugars, for example, are located on the genome in close proximity to other secondary-metabolite biosynthesis genes [J. F. Martin et al. (1989), Ann. Rev. Microbiol 43: 173-206].
In addition to this, it is known that a multiplicity of secondary metabolites from actinomycetes contain 6-deoxy sugar residues. Examples are, inter alia, aminoglycosides (e.g. spectinomycin, kasugamycin and streptomycin), polyenes (e.g. amphotericin A and B, and nystatin), macrolides (e.g. tylosin, erythromycin and avermectin), nucleosides (e.g. antibiotic A201A) and anthracyclines (e.g. daunorubicin and cytorhodin A) and glycopeptides (e.g. vancomycin) and isochromanequinones (e.g. granaticin).
The pathway for the biosynthesis of a 6-deoxy sugar residue of streptomycin, the L-dihydrostreptose residue, is depicted in FIG. 1.
Until recently, there were still no sequence data available for actinomycetes genes or enzymes which are involved in the biosynthesis of 6-deoxy sugars. As a result of cloning and analyzing the genes for the biosynthesis of streptomycin, it was possible to isolate and identify the genes for the 6-deoxy sugar component, L-dihydrostreptose: strD (dTDP-D-glucose synthase), strE (dTDP-D-glucose 4,6-dehydratase), strM (dTDP-4-keto-L-rhamnose 3,5-epimerase) and strL (dTDP-L-dihydrostreptose synthase) from Streptomyces griseus DSM40236.
The use of heterologous gene probes, i.e. gene probes which are employed for screening in another species or for isolating genes within another biosynthesis pathway, for the isolation of secondary-metabolite biosynthesis genes has thus far been limited to only a few genes (e.g. polyketide synthetase genes) [Nature (1987) 325: 818-821]. Using these polyketide synthetase gene probes, it is only possible to detect compounds which are formed via the polyketide synthetase biosynthesis pathway [C. L. Hershberger et al. (1989), Genetics and Molecular Biology of Industrial Microorganisms, Am. Soc. for Microbiol., Washington, D.C. 20005, pp. 76-78; S. L. Otten et al., J. Bacteriol. 172, No. 6 (1990), pp. 3427-3434], and not functionally different genes, such as aminoglycoside biosynthesis genes, for example.
It has now been found, surprisingly, that one or more gene probes from the strD, strE, strL or strM group of genes from Streptomyces griseus DSM40236, and structurally related genes, are suitable for use as gene probes for detecting the ge
REFERENCES:
Michael Stockmann et al., "Gene probes for the detection of 6-deoxyhexose metabolism in secondary metabolite-producing streptomycetes," FEMS Microbiology Letters 90 (1992) pp. 185-190.
J urgen Distler et al., "Gene cluster for streptomycin biosynthesis in streptomyces griseus: nucleotide sequence of three genes and analysis of transcriptional activity," Nucleic Acids Research, vol. 15, No. 19 (1987) pp. 8041-8057.
Dekker et al. (1991) J. Bacteriol. 173: 3078-3083.
Malpartida et al. (1987) Nature 325: 818-821.
Br au Barbara
Distler J urgen
Grabley Susanne
Piepersberg Wolfgang
Sichel Petra
Hobbs Lisa J.
Hoechst Aktiengesellschaft
Wax Robert A.
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