Anthracycline biosynthesis

Fujii I and Ebizuka Y (1997) Anthracycline biosynthesis in Streptomyces galilaeus. Chem Rev 97, 2511-2523. 

The anthracycline core is assembled from acetyl imits in the form of malonyl-CoA by an iterative, type II polyketide synthase (Metsa-Ketela et al. Anthracycline Biosynthesis Genes, Enzymes and Mechanisms , this volume) followed by aromatase, cyclase and tailoring enzymes, which produce the tetracycUc ring structure from the imstable polyketide chain as shown in Scheme 1. 

Biosynthetic modification of anthracycline biosynthesis has produced numerous new molecules, and its potential appears to be by no means exhausted. The research effort also reveals several instances of possible pitfalls, which may also be of interest when modifying other classes of antibiotic molecules Enzyme specificity. The substrate range of the introduced enzyme must include the intermediates available in the host but also the altered molecule must be a substrate for the host s downstream biosynthetic enzymes (as illustrated by the steffimycin hybrids). 

Keywords Anthracycline Biosynthesis Enzymology Polyketide Streptomyces... 

Table 1 Comparison of cloning methods of anthracycline biosynthesis gene clusters... 

Table 2 Anthracycline biosynthesis genes thus far identified... 

A major cause of the large structural diversity of the anthracyclines is the spectrum of oxidative tailoring reactions that is seen in the biosynthesis of these metabolites. It is noteworthy that a variety of mechanistically different oxygenases have been found in anthracycline biosynthesis, including flavoenzymes, cytochrome P450-type mono-oxygenases, a novel class of SAM-dependent hydroxylases as well as members of the family of cofactorless oxygenases. 

In spite of the large advances that have been made in the molecular biology, structural biology and enzymology of anthracycline biosynthesis in the last few years there are quite a few remaining questions that have not yet... 

Eritt I, Grafe U, Fleck FW. Inducers of both cytodifferentiacion and anthracycline biosynthesis of Sireptomyees gruetis and their occurrence in actinomycetes and other microorganisms. Allg Mikrobiol 1984 24 3-12. 

It is apparent, however, that glucose does not act to repress anthracycline biosynthesis by either. peucedus (261) or Screptomyces sp. strain C5 (Strohl WR and Dekleva ML, unpublished results), as considerable glucose remains in the media during the production phase. Inorganic phosphate, on the other haiKi, suppressed anthracycline biosynthesis in 5. peucedus (261). 

We have found recently that S. iividaTis TK24 (the most widely used host for cloning of anthracycline biosynthesis genes and one of the major cloning strains used in Strepto-myces research), as well as Strepromyces sp. strain C5, Srreptomyces cocfcolor A3(2), and S. peucen us ATCC 29050 all carry out the 13-oxo reduction of doxorubicin, daunorubicin, carminomycin, and idarubicin (as well as their lycones) to the respective 13-hydroxy species (244 Dickens ML and ohl WR, unpublished data). It is presumed at this time that perhaps multiple emymes can carry out this reduction. 

We sincerely thank Don Ordaz for assistance with the artwork, and C. Richard Hutchinson for several discussions on the biochemistry and molecular biology of anthracycline biosynthesis and for sharing unpublished data and ideas. Work on anthracycline biosynthesis in the Strohl laboratory, including all the unpublished work from the Strohl lab described herein, is funded by a grant (DMB-94-05730) from the National ScierKe Foundation. 

---