Post Polyketide Synthase Carbon–Carbon Bond Formation in Type-II PKS-Derived Natural Products from Streptomyces venezuelae

Abstract

Polyketide synthase (PKS) derived natural products are biosynthesized by head-to-tail addition of acetate and malonate extender units resulting in linear extended-polyketide chains. Despite the well-documented structural diversity associated with PKS-derived natural products, C-C chain branching deviating from the usual linear pattern is relatively rare. Herein, type-II PKS angucyclic natural products containing a hemiaminal functionality were identified and proposed as the parent of a series of C-C-branched analogues. These C-C linked acetate or pyruvate branching units were located at the α-positions on the extended polyketide chains of jadomycins incorporating 3- and 4-aminomethylbenzoic acids. Labeling studies utilizing [1-C]-d-glucose provided mechanistic evidence that the C-C bond formation occurred as a result of a previously unidentified post-PKS processing, additional to the enzymes encoded within the biosynthetic gene cluster. Selected compounds were evaluated in cytotoxic or antimicrobial assays.

The expansive library of jadomycins

“…Robertson et al proposed that these analogues were produced by trapping with primary metabolite cofactors, as there were no known post-PKS enzymes encoded in the jadomycin cluster predicted to catalyze this transformation. 33 Three corresponding 3-aminomethylbenzoic acid (3-AMBA) analogues (52p, q, s) were also reported in the study. 33 Similar carbon-branched analogues 53u and 54u were isolated from cultures using 7-aminoheptanoic or 8aminooctanoic acid.…”

“…33 Three corresponding 3-aminomethylbenzoic acid (3-AMBA) analogues (52p, q, s) were also reported in the study. 33 Similar carbon-branched analogues 53u and 54u were isolated from cultures using 7-aminoheptanoic or 8aminooctanoic acid. 27,35 Thus, when using linear alkyl amino acids, carbon-carbon bond formation at the 3a position became preferred as the chain length of the amino acids was extended since intramolecular cyclization of nine-membered and larger rings was found to be disfavoured.…”

“…Jd N (10, Figure 2A) was produced through the preferential cyclization of L-asparagine with the terminal amide over the carboxylic acid, giving a six-membered E-ring with 3a-R configuration. 4,13,16 Likewise, a dominant stereoisomer (>95% 3a-R configuration) had been observed during characterization of Jd S (33) and T (34), produced with L-serine and L-threonine, respectively. 4 Synthetic preparation of Jd S and Jd T aglycones by Akagi et al prompted a structural revision of the initially proposed oxazolone-ring containing structures, as their characterization substantiated the formation of an oxazolidine ring arising from cyclization of the side-chain hydroxyl groups.…”

“…A suite of jadomycin analogues have been isolated and characterized from cultures with amino acids where cyclization is unfavourable due to geometric constraints or intramolecular kinetics. 20,27,[33][34][35] Jd TFAL lactam (50p) was isolated with 27 in comparable yields. It was proposed that these compounds are produced through divergent mechanisms of B-ring cyclization, followed by oxidation at the C3a position to produce 50p.…”

“…well as substitution to give methoxy (51q), hydroxy (51r), acetate (51s), and pyruvate (51t) substituents. 33 The hydroxy (51r) and methoxy (51q) analogues were shown to interchange through solvolysis. The acetate (51s) and pyruvate (51t) analogues represent post-PKS carbon-carbon bond formation products that are unusual in type II polyketide biosynthesis.…”