Biosynthetic studies on the xanthone antibiotics lysolipins X and I

Abstract

Feeding experiments with 13C and 180-labeled precursors revealed that the molecular framework of the polycyclic xanthone antibiotics, the lysolipins X (1) and I (2), is derived from the polyketide pathway (12 malonate units), the Ci pool (methionine), molecular oxygen, and the nitrogen pool.Surprisingly, an intact malonate moiety serves as the three-carbon starter unit of the polyketide backbone, and 9 of the 12 oxygen atoms of 1 originate from molecular oxygen, including both of the xanthone oxygen atoms. The orientation of the malonate unit incorporated intact into lysolipin is unique and opposite from those in tetracycline and cycloheximide, i.e., the activated carbon of malonyl CoA is bound to the nitrogen of the lysolipin isoquinoline ring and the COa-derived carbon serves as the starter of the polyketide chain. From the biogenetic origin of the oxygen atoms several unusual prearomatic deoxygenation steps early in the biosynthesis have to be postulated.The polycyclic xanthone antibiotics form a small but distinct family of more than 20 members of microbial natural products. Their biological activities range from antibacterial (mainly Gram-positive bacteria including anaerobes,1-2 but also Gram-negative bacteria3), to anticoccidial,4 antifungal10•6 (e.g. yeasts, dermatophytes), and cytotoxic activities30•6 (e.g. HeLa cells).The lysolipins are antibacterial, antifungal (only 2), as well as cytotoxic compounds.3 After the albofungins,la~°t he lysolipins were the second group of the xanthone family of antibiotics to be discovered. These lipophilic antibiotics act lytically against cell walls, i.e., as inhibitors of cell wall biosynthesis (antagonism against lipid-bound mureine precursors).3® Lysolipin X (1) is the natural end product formed by Streptomyces violaceoniger (Tü 96) and the immediate precursor of lysolipin I (2), its dehydration product (Figure 1). While the absolute configuration of 2 could be established by X-ray analysis and chemical derivatization, the configuration of C-ll and C-12 in 1 is uncertain, because the instability of the molecule toward weak acids or light does not allow any chemical modificaf

Tuscolid and Tuscoron A and B: Isolation, Structural Elucidation and Studies on the Biosynthesis of Novel Furan‐3(2H)‐one‐Containing Metabolites from the Myxobacterium Sorangium Cellulosum

“…Malonate starter units were previously found for the macrolide-polyether antibiotic sorangicin A [11] produced by Sorancium cellulosum, strain So ce12, and for the lysolipins, [12] cycloheximide, [13] and tetracycline. [14] But neither the incorporation of [ 13 C]sodium hydrogen carbonate nor malonic acid was successful.…”

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

“…10 [189] and the decaketide Tfi96OR (273), unless one assumes a random effect on the chain length determining factor [190][191][192][193][194] of polyketide biosynthesis through the nitrosoguanidine mutagenesis experiment (for alternative possibilities see Sect. 10).…”

Isolation of the lysolipin gene cluster of Streptomyces tendae Tü 4042

“…It has structural similarities to pradimicin, (Oki et al, 1988) griseorhodin (Eckardt et al, 1978;Li and Piel, 2002), rubromycin (Brockmann et al, 1966), fredericamycin (a1) Formation of the polyketide chain from malonamide starter and malonate extenders; (b1) cyclization and reduction of polyketide precursor; alternatively, the incorporation of the amino group might occur at a later stage of biosynthesis (a2, b2); (c, d) Oxidative modification and "tailoring" of the intermediate; (e) spontaneous reduction of lysolipin X to lysolipin I and export. *O 2 from molecular oxygen; ▲ CH 3 from S-adenosylmethionine (SAM); ↔ malonate unit; ➞ acetate unit; A-G: ring nomenclature; 1-29: atoms involved in forming the lysolipin backbone (according to Bockholt et al, 1994). (Pandey et al, 1981), benastatin (Aoyagi et al, 1992) and some other large polyketides.…”