Biosynthesis of chrysomycins A and B origin of the chromophore.

Abstract

The biosynthetic origin of the carbon atoms in the chromophores of chrysomycins A and B was investigated in feeding experiments using 13C labeled acetates and propionate.A biosynthetic scheme is proposed involving the condensation and rearrangement of a decaketide intermediate which contains either propionate (chrysomycin A) or acetate (chrysomycin B) as the chain initiator.The isolation of chrysomycin was first reported in 1955 by STRELITZ and coworkers1) who were screening for antibiotics with activity against bacteriophages.Although the physico-chemical properties of this antibiotic, including a highly characteristic absorption spectrum, were published, no structure was established. Subsequently, several related antibiotics containing very similar, if not identical, chromophores were described: toromycin2), virenomycin3), gilvocarcin4) and ravidomycin5)'.The first member of this group of related antibiotics to have its structure determined was toromycin6), which was shown to consist of a substituted naphthalene chromophore with a sugar moiety attached by a carbon-carbon glycosyl bond. Structures for other members of this group quickly followed7~9), and all contained the same tetracyclic chromophore. Gilvocarcin V proved to be identical to toromycin as also did other antibiotics'10~12). Although a detailed comparison has not been possible, it seems likely that virenomycin has the same structure as chrysomycin. Both chrysomycin and gilvocarcin occur in microbial fermentations as a mixture of two analogues that differ only in having a vinyl (chrysomycin A and gilvocarcin V) or methyl (chrysomycin B and gilvocarcin M) substituent on the chromophore. In the case of ravidomycin only the vinyl analogue has been described. The structures of chrysomycin, gilvocarcin and ravidomycin are shown in Fig. 1. Although toromycin is the preferred name for 3, the only biosynthetic studies reported for this compound were done using Streptomyces gilvotauareus13), hence in this paper we refer to this antibiotic as gilvocarcin V. Recently we reported on the biosynthesis of ravidomycin14) and proposed a scheme in which a single decaketide chain initiated by propionate gave rise to the chromophore via a tetracyclic intermediate from which two carbons are lost. TAKAHASHI and TOMITA13) have published results on the biosynthesis of gilvocarcins V and M, and proposed a scheme that differs significantly from that for ravidomycin. The key difference between the two biosynthetic schemes concerns the C-8 vinyl substituent. In the case of ravidomycin, it derives from propionate, which is suggested to be a polyketide chain initiator and retains its carboxyl as part of the chromophore. Although the gilvocarcin scheme also proposes a propionate origin, it is a secondary substituent added to a pre-existing ring system with loss of its associated carboxyl group. According to this latter scheme gilvocarcin M was synthesized by substituting the chromophore with acetate rather than propionate, again with concomitant loss of the carboxyl group.

Angucyclines: Total syntheses, new structures, and biosynthetic studies of an emerging new class of antibiotics

“…Also the very !nteresting antitumor antibiotics of the gilvocarcin class [226][227][228][229][230][231][232][233][234][235][236][237][238][239][240][241] The key biosynthetic step is an oxidative cleavage of the 6a,7-bond of an angucyclinone, presumably ochromycinone (35) ravidomycin (293), the chrysomycins A (294), and B (295), and thus BE-12406 A (296) and B (297, see Table 15), are all thought [226,229,230] to derive from a decaketide folded in the typical angucyclinone manner. Similarly as shown for the kinamycins and jadomycins, an oxidative C-C bond cleavage initiates excision of a single carbon, and further rearrangement leads to the typical lactone structures of the gilvocarcin class.…”

Cloning and Characterization of the Ravidomycin and Chrysomycin Biosynthetic Gene Clusters

“…Incorporation experiments showed that the gilvocarcin, ravidomycin, and chrysomycin backbone derived from acetate and propionate, and it was suggested that the pathway involves an oxidative rearrangement of an angucyclinone intermediate. [31–33] We recently isolated the GV gene cluster and characterized various genes through inactivation and cross complementation experiments. [14,34–37] However, our efforts to address the biosynthetic sequence of key post-PKS tailoring events and their relevant intermediates were hampered by the resistant nature of the producer strain for genetic manipulations, and the inability of several mutant constructs to express in a heterologous host.…”

Variability of Seyfert galaxies in the near-infrared — II. The unusual starburst Seyfert NGC 7469

“…NGC 7469 is also a noted example of variability amongst Seyfert galaxies. UBV or UBVR photometry has been undertaken in the Crimea since 1967 (Doroshenko, Lyutyi & Rakhimov 1989, 1990Chuvaev, Lyutyi & Doroshenko 1990). Shorter series of observations have been made by Penston et al (1974) and Penfold (1979).…”