Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin

Abstract

Only a handful of aziridine-containing natural products have been identified out of the more than 100,000 natural products characterized to date. Among this class of compounds, only the azinomycins (azinomycin A and B) and ficellomycin contain an unusual 1-azabicyclo[3.1.0]hexane ring system, which has been reported to be the reason for theDNAcrosslinking abilities and cytotoxicity of these metabolites. Both families of natural products are produced by Streptomyces species, Streptomyces sahachiroi and Streptomyces ficellus, respectively. Up until recently, much of the work on these molecules has focused on the synthesis of these natural products or their corresponding analogs for in vitro investigations evaluating their DNA selectivity. While one of the most intriguing aspects of these natural products is their biosynthesis, progress made in this area was largely impeded by difficulties with obtaining a reliable culture method and securing a consistent source of these natural products. In this review, we will cover the discovery and biological activity of the azinomycins, their mode of action, related synthetic analogs and biosynthesis, and finish with a discussion on the less studied metabolite, ficellomycin.

Polyketide Ring Expansion Mediated by a Thioesterase, Chain Elongation and Cyclization Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG

“…3,19 In vivo experiments on this PKS have suggested that AziB alone is responsible and sufficient for the biosynthesis of 5-methylnaphthoate. 20 The AziB protein was successfully cloned and overexpressed in E. coli giving a 187 kDa His-tagged apo -enzyme form of the PKS that was successfully purified by Ni-NTA chromatography (Fig.…”

“…3 In an early phase clinical investigation, azinomycin B has shown favorable results against 36 cases of malignant neoplasms, with the most promising effects observed against squamous cell carcinoma. 4 In vitro studies suggest their biological activity resides in their ability to cross-link double stranded DNA through the actions of the electrophilic aziridine and epoxide moieties of the molecule.…”

“…The 3′-methoxy group of the naphthoate is generated by oxidation and methylation as mediated by tailoring enzymes. 3 …”

Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by Streptomyces sahachiroi

“…Here, we have carried out a functional knockout of aziA2 within the azinomycin gene cluster of Streptomyces sahachiroi [11–12]. The gene encodes a NRPS (non-ribosomal peptide synthetase, an enzyme involved in the biosynthesis of various peptide containing secondary metabolites) module of unusual domain architecture consisting of condensation, peptidyl carrier protein, and condensation domains (C-PCP-C), respectively.…”

DNA Alkylating Agents

“…For instance, azinomycin B (carzinophilin) is a complex natural product isolated from Streptomyces sahachiroi that contains densely assembled functionalities and has potent antitumor activity due to DNA intercalation and interstrand cross-linking ( Figure 5.25). 57,58 It was used with some success in a clinical study in humans with several types of cancer.…”