Molecular Lego: Polyketides represent a highly diverse group of natural products with structurally intriguing carbon skeletons (see picture) which are assembled from simple acyl building blocks. A combination of chemical, biochemical, and genetics studies have provided exciting new insights into the programming of polyketide assembly and the sophisticated enzymatic machineries involved. This review highlights recent developments in the field.Polyketides constitute one of the major classes of natural products. Many of these compounds or derivatives thereof have become important therapeutics for clinical use; in contrast, various polyketides are infamous food-spoiling toxins or virulence factors. What is particularly remarkable about this heterogeneous group of compounds comprising of polyethers, polyenes, polyphenols, macrolides, and enediynes is that they are mainly derived from one of the simplest building blocks available in nature: acetic acid. Investigations at the chemical, genetic, and biochemical levels have shed light on the biosynthetic programs that lead to the large structural diversity of polyketides .This review highlights recently unveiled biosynthetic mechanisms to generate highly diverse and complex molecules.

The Biosynthetic Logic of Polyketide Diversity

Many drug candidates from marine and terrestrial invertebrates are suspected metabolites of uncultured bacterial symbionts The antitumor polyketides of the pederin family, isolated from beetles and sponges, are an example Drug development from such sources is commonly hampered by low yields and the difficulty of sustaining invertebrate cultures To obtain insight into the true producer and find alternative supplies of these rare drug candidates, the putative pederin biosynthesis genes were cloned from total DNA of Paederus fuscipes beetles, which use this compound for chemical defense Sequence analysis of the gene cluster and adjacent regions revealed the presence of ORFs with typical bacterial architecture and homologies The ped cluster, which is present only in beetle specimens with high pederin content, is located on a 54-kb region bordered by transposase pseudogenes and encodes a mixed modular polyketide synthase/nonribosomal peptide synthetase Notably, none of the modules contains regions with homology to acyltransferase domains, but two copies of isolated monodomain acyltransferase genes were found at the upstream end of the cluster In line with an involvement in pederin biosynthesis, the upstream cluster region perfectly mirrors pederin structure The unexpected presence of additional polyketide synthase/nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederin-type pathways in beetles and sponges

https://www.pnas.org/content/pnas/99/22/14002.full.pdf

A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(12)00007-5.pdf

Lessons from the Past and Charting the Future of Marine Natural Products Drug Discovery and Chemical Biology

Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork

In mammals, cadmium is widely considered as a non-genotoxic carcinogen acting through a methylation-dependent epigenetic mechanism. Here, the effects of Cd treatment on the DNA methylation patten are examined together with its effect on chromatin reconfiguration in Posidonia oceanica. DNA methylation level and pattern were analysed in actively growing organs, under short- (6 h) and long- (2 d or 4 d) term and low (10 mM) and high (50 mM) doses of Cd, through a Methylation-Sensitive Amplification Polymorphism technique and an immunocytological approach, respectively. The expression of one member of the CHROMOMETHYLASE (CMT) family, a DNA methyltransferase, was also assessed by qRT-PCR. Nuclear chromatin ultrastructure was investigated by transmission electron microscopy. Cd treatment induced a DNA hypermethylation, as well as an up-regulation of CMT, indicating that de novo methylation did indeed occur. Moreover, a high dose of Cd led to a progressive heterochromatinization of interphase nuclei and apoptotic figures were also observed after long-term treatment. The data demonstrate that Cd perturbs the DNA methylation status through the involvement of a specific methyltransferase. Such changes are linked to nuclear chromatin reconfiguration likely to establish a new balance of expressed/repressed chromatin. Overall, the data show an epigenetic basis to the mechanism underlying Cd toxicity in plants.

/pdf/in-posidonia-oceanica-cadmium-induces-changes-in-dna-3cu7uj83mr.pdf

In Posidonia oceanica cadmium induces changes in DNA methylation and chromatin patterning

Cloning, sequencing and analysis of the enterocin biosynthesis gene cluster from the marine isolate 'Streptomyces maritimus': evidence for the derailment of an aromatic polyketide synthase.

Mark S Newman

Papers

Cloning, sequencing and analysis of the enterocin biosynthesis gene cluster from the marine isolate 'Streptomyces maritimus': evidence for the derailment of an aromatic polyketide synthase.