Chemical and biosynthetic evolution of the antimycin-type depsipeptides

Abstract

Evolution of natural products, and particularly those resulting from microbial assembly line-like enzymes, such as polyketide (PK) and nonribosomal peptides (NRP), has resulted in a variety of pharmaceutically important and chemically diverse families of molecules. The antimycin-type depsipeptides are one such grouping, with a significant level of diversity and members that have noted activities against key targets governing human cellular apoptosis (e.g. Bcl-xL and GRP78). Chemical variance originates from ring size, with 9-, 12-, 15-, and 18-membered classes, and we show that such distinctions influence their molecular targeting. Further, we present here a systematic interrogation of the chemistry and assembly line evolution of antimycin-type analogues by conducting metabolomic profiling and biosynthetic gene cluster comparative analysis of the depsipeptide assembly lines for each member of the antimycin-group. Natural molecular evolution principles of such studies should assist in artificial re-combinatorializing of PK and NRP assembly lines.

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

“…11). Although bioinformatics analysis has shown high sequence similarity among the AT domains of all four PKSs, 8 AntD-AT incorporates alkyl extender units into the macrocycle while the AT domains of the other three PKSs likely select malonate or methylmalonate, which then undergoes methylation by the MT domain. However, the number of modules in the NRPS-PKS assembly line of each of the four classes of antimycin-type depsipeptides differs, resulting in the variation in macrolactone ring size.…”

“…Since their initial isolation in 1949, 1 antimycin-type depsipeptides have received considerable interest because of their potent and diverse biological activities. [9][10][11] It will also discuss the recent identication and characterization of hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly lines responsible for the biosynthesis of antimycin-type depsipeptides, 8,12 which has prompted the generation of a signicant number of new antimycin analogues. 2 More recently, several classes of antimycin-type depsipeptides have also been shown to have promising anti-cancer and anti-inammatory activities.…”

Rare Streptomyces N-Formyl Amino-salicylamides Inhibit Oncogenic K-Ras

“…8 Isolated in 1967 from a South American soil isolate of Streptomyces (formerly Streptoverticillium ) orinoci , 7c the partial configuration of neoantimycin was assigned in 1969 by preparative-scale (1 g) degradation that yielded methyl ( S )-2-hydroxyisovalerate and methyl (2 S ,3 S )-2-hydroxy-3-methyl-valerate. 7b At that time an L-Thr configuration was also asserted, but not proven.…”

The regulation and biosynthesis of antimycins

“…The gene clusters for JBIR-06 (12-membered ring), neoantimycin (15-membered ring), and 18-membered ringed respirantin were recently identified [43–44]. JBIR-06 and neoantimycin inhibit GRB78 chaperone involved in the unfolded protein response [45–46].…”

“…JBIR-06 and neoantimycin inhibit GRB78 chaperone involved in the unfolded protein response [45–46]. Although the DNA sequence for the gene clusters for these ring-expanded antimycins has not yet been made publically available, they all encode the machinery necessary to assemble the 9-membered antimycin core suggesting a common evolutionary past [44]. The vast chemical diversity in the antimycin family together with the recent characterisations of the promiscuous biosynthetic machinery suggest it is possible to use synthetic biology to bioengineer non-natural analogues in large enough quantity to test their efficacies in the clinic.…”