Polyketides daunorubicin

VB Rajgarhia, WR Strohl. Minimal Streptomyces strain C5 daunorubicin polyketide biosynthetic genes required for aklanonic acid biosynthesis. J Bacteriol 179 2690-2696, 1997. 

Scheme 13. The antitumor antibiotics daunomycin (29 = daunorubicin) and adiiamycin (30 = doxorubicin) are polyketides with an attached deox ugar moiety. Polyketide oligodeoxy-saccharides characterized by one or more deoxysaccharide chains include the anthracyclines arugomycin (31) [73a] and viriplanin (32), the angucyclines landomycin A (see 12 in Scheme 6) and vineomycin A, (33 = P1894B [74]), and the aureolic acid antibiotics mithramycin (34) and UCH9 (35).Also,orthosomydn antibiotics, such as avUamycin A (36) can be considered as polyketide oligodeoxysaccharides...

Methyl transfer reactions play a significant part in the modifications of aromatic polyketides, both of the polyketide core [61,62] as well as of several of the sugar moieties [44,53]. In Streptomyces, more than 20 amino acid sequences have been found that may represent enzymes involved in methyl transfer reactions in the biosynthesis of aromatic polyketides [149]. One of these enzymes, the S-adenosyl-L-methionine-dependent DnrK, is involved in the methylation of the C-4 hydroxyl group in daunorubicin/doxorubicin biosynthesis (Scheme 10, step 12). The subunit of the homo-dimeric enzyme displays a fold typical for small-molecule methyltransferases. The structure of the ternary complex with bound products S-adenosyl-L-homocysteine and 4-methoxy-8-rhodomycin provided insights into the structural basis of substrate recognition and catalysis [149]. The position and orientation of the substrates suggest an Sn2 mechanism for methyl transfer, and mutagenesis experiments show that there is no catalytic base in the vicinity of the substrate. Rate enhancement is thus most likely due to orientational and proximity effects [149]. 

These experiments together indicate two parallel, and overlapping, aspects of daunorubicin PKS function (a) the products of the two downstream genes (dpsCD) arc not required for formation of the polyketide precursor initiated with pnopionyl-SCoA and (b) in the absence of dpsCD, the PKS complex is slc ier, namely, it accepts both acetyl and propionyi starter units. This suggests that the presence of dpsCD ensures that... 

Meuter G, Hutchinson CR. Daunorubicin Type il polyketide synthase enzymes DpsA and DpsB determine neither the choice of starter unit nor the cyclization pattern of aromatic polyketides. ] Am Chem Soc 1995 117 5899-5900. 

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