Process for producing anthracyclines and intermediates thereof

Details Process for producing anthracyclines and intermediates thereof Process for producing anthracyclines and intermediates thereof

1997-03-27

1999-11-16

Degen, Nancy

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

435 41, 435128, 4353201, C07H 2104, C12P 104, C12N 1531, C12N 1576

Patent

active

059860774

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

The present invention pertains to a process for producing anthracyclines and intermediates thereof by expressing in a foreign host a DNA fragment relating to the biosynthetic pathway of anthracyclines and, if desired, the intermediates obtained are converted to anthracyclines or aglycones thereof using non-producing mutant strains.


RELATED ART

Polyketide antibiotics are a broad and variable group of compounds which are composed of poly-.beta.-ketomethylene chain [CHRO].sub.4-20. A common feature of poly-ketides is their biosynthetic route which is similar to the biosynthesis of fatty acids. Katz, L. and Donadio, S. (1993) have recently published a review article concerning polyketides. As their structure the antibiotics of anthracycline group are aromatic polyketides, the common structural body of which is 7,8,9,10-tetrahydro-5,12-naphthacene kinone of the general formula (A) ##STR1##
To this structural body one or more sugars and other substituents are attached. The structural body of the molecule, to which the sugars are attached, is called an aglycone. Anthracyclines are discussed more specifically e.g. in the article of A. Fujiwara and T. Hoshino (1986). Several anthracyclines are cytostatically active and thus they are of continuous interest.
To find new anthracyclines screening of Streptomyces bacteria from the soil and mutation thereof are used. To modify known anthracyclines synthetic methods have been used, whereby chemical groups are added to or removed from either the aglycone or the sugar moiety. Similarly, biotransformation is used, wherein in living cells molecules are modified which have been produced by other production strains or by synthetic methods. Some anthracyclines have also been produced by synthetic methods.
The hybrid antibiotic technology has been disclosed as a new technology in the preparation of new antibiotics. It has been established to comprise production by genetic engineering of molecules which have structural features of natural products of two strains. The process is described in the publication of H. G. Floss: "Hybrid antibiotics--the contribution of the new gene combinations" (1987). The hybrid antibiotic technology gives an opportunity to controlled production of new compounds.
Cloning of actinorhodin genes from Streptomyces coelicolor (Hopwood et al., 1985) can be considered as the pioneer work in the molecular biological study of polyketide antibiotics and at the same time of streptomycetes. In 1987 Malpartida et al. reported about the hybridization of different polyketide producers to the actI and actill DNA fragments and thereafter genes of the polyketide synthase (PKS) domain have been identified in many Streptomyces species exploiting the homology. Sequencing of these genes has shown that the genes are strongly conserved and include three Open Reading Frames, ORF 1, 2 and 3. The products of these three genes are needed for the formation of the linear polyketide bound to the enzyme complex. For the optimal formation of the correct product encoded by the PKS-genes five ORFs are needed in tetracenomycin (Shen and Hutchinson, 1993). The sequenced aromatic PKSs are given in Table 1.


TABLE 1 ______________________________________ Cloned and sequenced gene domains encoding polyketide synthase of aromatic polyketide antibiotics Strain Product Reference ______________________________________ S. coelicolor aktinorhodin Fernandez-Moreno, M. A. et al. 1992 Hallam, S. E. et al. 1988 S. violaceoruber granaticine Sherman, D. H. et al. 1989 S. glaucescens tetracenomycin Bibb, M. J. et al. 1989 S. rimosus oxitetracycline Kim, E-S. et al. 1994 S. cinnamonensis monoensine Arrowsmith, T. J. et al. 1992 S. griseus griseusine Yu, T-W. et al. 1994 S. roseofulvus frenolisine Bibb, M. J. et. al. 1994 ______________________________________
Polyketide synthase (PKS) is a multienzyme complex which functionally reminds the synthase of long chain fatty acids. The separate components of actinorhodin PKS are so called actO

REFERENCES:
patent: 5364781 (1994-11-01), Hutchinson et al.
patent: 5672491 (1997-09-01), Khosla et al.
Lampel et al., Transformation and Transfection of Anthracycline-Producing Streptomyces. Applied and Environmental Microbiology. 51 (1): 126-131, Jan. 1986.
Niemi et al. Hybrid Anthracycline Antibiotics: Production of New Anthracyclines by Cloned Genes from Streptomyces purpurascens in Streptomyces galilaeus. Microbiology. 140 (6): 1351-1358, May 1994.
Bibb, Mervyn J. et al., "Analysis of the nucleotide sequence of the Streptomyces glaucescens tcml genes provides key information about the enzymology of polyketide antibiotic biosynthesis", EMBO Journal, vol. 8, No. 9, pp. 2727-2736 (1989).
Yu, Tin-Wein et al., "Cloning, Sequencing, and Analysis of the Griseusin Polyketide Synthase Gene Cluster from Streptomyces Griseus", Journal of Bacteriology, vol. 176, No. 9, May 1994, p. 2627-2634 (1994).
Malpartida, F. et al., "Homology between Streptomyces Genes Coding for Synthesis of Different Polyketides used to Clone Antibiotic Biosynthetic Genes", Nature, vol. 325, pp. 818-821 (1987).
McDaniel, Robert et al., "Engineered Biosynthesis of Novel Polyketides" Science, vol. 262, pp. 1546-1550 (1993).
McDaniel, Robert et al., "Engineered Biosynthesis of Novel Polyketides: Manipulation and Analysis of an Aromatic Polyketide Synthase with Unproven Catalytic Specificites" American Chemical Society, vol. 115, pp. 11671-11675 (1993).
Stutzman-Engwall, Kim J., "Multigene Families for Anthracycline Antibiotic Production in Streptomyces Peucetius" Natl. Acad. Sci. USA, vol. 86, pp. 3135-3139 (1989).

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