Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

Abstract

Diverse actinomycetes produce a family of structurally and biosynthetically related non-ribosomal peptide compounds which belong to the chromodepsipeptide family. These compounds act as bisintercalators into the DNA helix. They give rise to antitumor, antiparasitic, antibacterial and antiviral bioactivities. These compounds show a high degree of conserved modularity (chromophores, number and type of amino acids). This modularity and their high sequence similarities at the genetic level imply a common biosynthetic origin for these pathways. Here, we describe insights about rules governing this modular biosynthesis, taking advantage of the fact that nowadays five of these gene clusters have been made public (thiocoraline, triostin, SW-163 and echinomycin/quinomycin). This modularity has potential application for designing and producing novel genetic engineered derivatives, as well as for developing new chemical synthesis strategies. These would facilitate their clinical development.

Molecular Networking and Pattern-Based Genome Mining Improves Discovery of Biosynthetic Gene Clusters and their Products from Salinispora Species

“…Assignment of the unknown amino acid revealed a threonine moiety, a previously unprecedented residue in the quinomycin family. The characterized members of this family contain D-serine (echinomycins), D-cysteine (thiocoralines), or D-diaminobutyric acid (quinaldopeptin) at this position (Fernández, et al, 2014). Marfey’s analysis of the hydrolyzed compound showed the stereochemistry of the threonine residue to be D- allo -Thr, which corresponds to the presence of an epimerase domain in the first module of RtmO.…”

Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans

“…Ethidium displacement by molecules, such as chemotherapeutics [ 54 ] or flavonoids [ 47 ], could decrease the ethidium fluorescence signal, making the interpretation of data difficult.…”

Evaluating the Effects of an Organic Extract from the Mediterranean Sponge Geodia cydonium on Human Breast Cancer Cell Lines

“…Marine amino acid derivatives and peptides have been shown to possess interesting biological properties; in particular, they have attracted much attention due to their high specificity against cancer cell lines [ 27 ]. 3-HQA in cluster (c) is found in several bisintercalator natural products of marine origin (such as thiocoraline, triostin, SW-163 and echinomycin/quinomycin) [ 28 ], as one of the two key chromophores (together with quinoxalinic acid) for binding to duplex DNA by insertion between the bases to allow proper placement of the peptidic core into the DNA minor groove [ 29 ]. Phosphatidylethanolamine (PE) in cluster (d) belongs to the family of phospholipids and glycolipids that are the main constituents of sponge cell membranes [ 30 , 31 ], and have been shown to possess immune-modulating and antitumor activity [ 32 , 33 ].…”