Biosynthesis of fredericamycin A, a new antitumor antibiotic

Abstract

Fredericamycin A (FM A), produced by a strain of Streptomyces griseus, represents a new structural class of antitumor antibiotics containing a spiro ring system. Studies on the producer organism showed that glucose in the fermentation medium is not utilized until late in the growth stage, just prior to synthesis of FM A. [14C]Glucose tracer experiments demonstrated that glucose is incorporated into FM A by catabolism to acetate. Biosynthetic enrichment of FM A with single- and double-labeled [13C]acetate showed that the entire carbon skeleton of the spiro ring system is derived from acetate. L-Methionine was shown to provide the only nonskeletal carbon in FM A, the methoxy carbon at position C-6. The direction of the polyketide chain and the position of the carbon lost during biosynthesis were established by using stable isotope experiments. A general model for FM A biosynthesis is proposed, and a possible scheme for the formation of the spiro carbon center is presented.

In Vivo Investigation of the Roles of FdmM and FdmM1 in Fredericamycin Biosynthesis Unveiling a New Family of Oxygenases

“…These features of 1 heighten the interest in investigations of the biosynthetic pathway for this unique natural product. Feeding experiments (20) and cloning of its biosynthetic gene cluster confirm the polyketide origin of 1 (12). Characterization of intermediates 8, 9, and 10 unveils the final steps en route to 1 and suggests that its carbaspirocycle moiety is formed through a benzilic acid rearrangement process from 10 to 1 (Fig.…”

Identification of Fredericamycin E from Streptomyces griseus: Insights into Fredericamycin A Biosynthesis Highlighting Carbaspirocycle Formation

“…An oxidative ring contraction mechanism supported by the results of isotope-labeling experiments has been proposed previously to account for the net loss of the C-18 carbon of 3 ( Figure 1A). 4 Oxidative ring contraction was also supported by our previous identification of two pathway-specific oxygenases, FdmL and FdmK, to which other oxidation steps to 1 biosynthesis could not be attributed. 18 Importantly, while different mechanisms for oxidative ring fission or contraction have been proposed for the biosynthesis of polyketide natural products such as gilvocarcin, 19 jadomycin, 20 griseorhodin, 21 and kinamycin, 22 little is known about carbaspirocycle biosynthesis.…”

“…The biosynthetic origin of 1 was established by isotope-labeling experiments, and this compound was proposed to be a pentadecaketide derived from sequential condensations of 15 malonyl-CoAs with C-29/C-30 representing the starter acetate unit ( Figure 1A). 4 FDM A (1) has moderate antibacterial and antifungal activities but is most notable for its potent activity against P388 mouse leukemia, CD8F mammary tumors, and B16 melanoma in vivo. 5 The antitumor activity of 1 likely results from multiple mechanisms of action that are, at least partly, attributable to the unique molecular topology resulting from the unprecedented C-5 spirocyclic fusion ( Figure 1A).…”

A Biosynthetic Classification of Fungal and Streptomycete Fused-Ring Aromatic Polyketides

“…The unusual labelling of the spirocyclopentane rings of the [ 13 C 2 ]acetate-derived streptomycete metabolite fredericamycin A (57) appears to favour its formation from two polyketide chains. [78] However, a single-chain pathway may be envisaged involving an oxidative rearrangement with two sequential 1,2-shifts of the mode-S-folded pentacarbocyclic pentadecaketide intermediate 58 related to benastatin A (59), [79] as shown in Scheme 8. [80] The recently revised structure of the streptomycete polyketide b-rubromycin (60) [81] and the mode of incorporation of [U-13 C 3 ]malonate is also accommodated by this scheme.…”