Streptovaricin biosynthesis

Streptovaridns and Mitomycins.—Consideration of the structures deduced for metabolites with the streptovaricin skeleton which lack in particular the extensive oxygenation of say streptovaricin D, has allowed a reasonable sequence of events for streptovaricin biosynthesis to be proposed. (The streptovaridns belong to the class of ansamydns. For earlier reviews on ansamycin biosynthesis see ref. 5, p. 52, and ref. 6, p. 45.)... 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

Investigations of the biosynthesis of the rifamycins, streptovaricins and geldanamycin proved that the ansa chain of the ansamycins is synthesized as proposed by Woodward. The isolation of the precursors rifamycin W, damavaricin C and D and the protostreptovaricins, together with the fact that rifamycin B and tolypomycin Y are cosynthesized by Streptomyces tolypophorus26 make it probable that the rifamycins, streptovaricins and tolypomycin Y have a common progenitor. 

Using carbon-13 magnetic resonance spectroscopy, Rinehart and his collaborators have shown49 that the biosynthesis of the streptovaricins is very similar to that of the rifamycins. Streptovaricin D is synthesized from a C7N unit of unknown origin to which 8 propionic acid residues and two acetic acid residues are attached, whereby the direction of growth is the same as that of the rifamycins. In contrast to the... 

As possible biogenetic precursors of the streptovaricins, damavaricin C and D and the protostreptovaricins I-V have been isolated and characterized (Fig. 8)21,22. Streptovaricin C and D are the precursors of the other streptovaricins22. Figure 13 summarizes the various supposed routes of biosynthesis of the streptovaricins. 

Studies using 14C-labelled precursors and C-l3 carbon magnetic resonance have suggested that the biosynthesis of the benzenic ansamycin geldanamycin follows essentially the same pathway as that of the rifamycins and streptovaricins50. Geldanamycin is composed of 3 acetate and four propionate units which are attached to a C7N unit in the same direction of growth as is found in rifamycins and streptovaricins. The incorporation of three acetate units into the ansa chain, as opposed to two in the naphthalenic ansamycins, excludes the existance of a common precursor. 

Unambiguous assignment of the C NMR spectrum of streptovaricin C (44) was achieved and the biosynthesis of this compound was studied [93]. The configurations of the eight chiral centers, C-20 (C-6) to C-27 (C-23), and ansa system of the streptovaricins were reported [94], and the absolute configuration of 44 reported in 1971 [92] was revised in this paper [94]. 

It was also found that when [r- C]-AHBA (118) was administered to a streptovaricin C (44) producing culture, C-21 (the quinone methide carbonyl at 188.3 ppm) of 44 was specifically labelled (Fig. 5) [93], and the existence of 118 itself in the fermentation broth was reported [186,187]. It was also reported that the biosynthesis of the naphthalenoid ansamycin antibiotic actamycin (69) was markedly increased by the... 

The origin of the ansa chain and the direction of the synthesis of geldanamycin (85) were reported [139]. According to the report, the ansa chain consists of acetic and propionic acid moieties, and the direction of the biosynthesis was through the amide-head pathway, like that of streptovaricin D (45) (Fig. 10) [91]. It was also reported that two C2 units of the ansa moiety of geldanamycin (85) at C-5-C-6 and C-1 l-C-12 arose from two glycolate (G) units [177]. Consequently, the biosynthetic building units and their sequence on 85 are indicated as P-A-G-P-P-G-P (the P unit corresponds to a C-1 carbonyl, C-2 and a methyl at C-2). 

The derivative examined by x-ray was, in fact, the atropisomer of the natural streptovaricin C derivative the subject of atropisomerism will be discussed in detail in Section III.A.l. Structures of the other streptovaricins rest mainly on comparison of their spectral properties to those of streptovaricin C. Streptovaricins B and J have also been related to streptovaricin C by acetylation (103 streptovaricin A to streptovaricins G and K by acetylation (103), streptovaricin E to streptovaricin C by reduction (103 streptovaricin G to streptovaricin by lactonization (56), and streptovaricin C to streptovaricins A, D, and G by biosynthetic conversion. (The latter topic will be discussed in Section V.A, dealing with Biosynthesis.)... 

U- C]phenylalanine, and [4- C]erythrose hardly at all. [Carboxy- C]-propionate, [methylene- C]ma onaXe, and [m //7jr/- C]methionine were then administered and the carbons labeled were identified, employing the carbon assignments made previously (see Table 5), in the cmr spectra of the labeled streptovaricin D (the most abundant streptovaricin found in the biosynthetic studies). Results showed that [f /r/70A 3 - C]propionate labels eight carbon atoms to approximately the same extent, C-1, C-5, C-7, C-9, C-11, C-13, C-15 and C-19, thus establishing the amide-head direction of biosynthesis (Scheme a) (90). By implication, carbons C-2, C-6, C-8, C-10, C-12, C-14, C-16, and C-20, plus the 2-, 6-, 8-, 10-, 12-, 14-, 16- and 20-methyl carbons were also derived from propionate. Sodium [2- C]malonate labeled equally C-4 and C-18 (by implication, carbons C-3 and C-17 were also derived from malonate), which further... 

Thus, the three ansamycins whose biosyntheses have been investigated are derived from closely related biosynthetic pathways. The streptovaricin and rifamycin ansa chains are derived from seven propionate and two acetate (malonate) units, the geldanamycin ansa chain from four propionate, one malonate and two still unidentified 2-carbon units. In two of the three antibiotics (and presumably in streptovaricin as well) a C7N unit is derived from glucose via a shikimate-type pathway. Although a number of late intermediates in the biosynthesis of rifamycin and streptovaricins have been identified, much remains to be done. 

Milavetz, B. I. Biosynthesis of the Streptovaricins. Ph.D. Thesis, University of Illinois, Urbana, Illinois, 1975. 

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