The enterocins (1–3) and wailupemycins (4–10) were the first marine actinomycete natural products for which a complete gene cluster was identified, sequenced, and verified (). These molecules comprise more than half a dozen structurally-related aromatic polyketides isolated from a sediment-derived marine actinomycete identified as “Streptomyces maritimus”. The enterocins and wailupemycins drew the interest of researchers in part because of their unique polyketide carbon skeletons, which labeling studies during the mid-1970s revealed were derived from an uncommon benzoate starter unit along with seven malonate extender units that underwent a Favorskii-like rearrangement to yield the observed range of carbon skeletons. More than twenty years after labeling-based insights were obtained, the genetic basis for biosynthesis of these natural products was finally unveiled and revealed information unattainable through strictly chemical-based studies.
Whole genome sequencing of producing organisms, especially bacteria and fungi, reveals that we have discovered only a fraction of these biosynthetically derived small molecules; a substantial fraction of natural product chemical space still represents “dark matter” (i.e., molecules predicted by bioinformatics analysis that have yet to be observed experimentally).
Natural Product Reports - Royal Society of Chemistry
Amy L. Lane Amy L. Lane graduated summa cum laude with a B.S. in chemistry from Indiana State University in 2003. She then completed graduate research in the laboratory of Prof. Julia Kubanek at Georgia Institute of Technology, exploring the ecological functions and drug discovery potential of marine macroalgal natural products and earning a Ph.D. in chemistry in 2008. From 2008–2010, she pursued a National Institutes of Health (NIH) postdoctoral fellowship at Scripps Institution of Oceanography in the laboratory of Prof. Bradley S. Moore, where she completed studies on the biosynthesis of marine actinomycete natural products. She is presently an assistant professor of chemistry at the University of North Florida. Her current research interests involve application of genetic and chemical tools toward discovery of marine natural products and understanding their ecological functions.
natural products: occurrence, biosynthesis…
The last decade was a revolutionary period for the field of marine natural product biosynthesis. During this time, the field emerged from one technologically dominated by chemical labeling methods to one capitalizing on advancements in molecular biology, genetics, bioinformatics, and other biological disciplines. Increases in speed and decreases in cost of DNA sequencing, population of public databases with vast amounts of gene and protein information,- and other advances in the biological sciences made possible great strides in understanding the biosynthesis of marine molecules during 2000 through mid-2010. As a result of such biological advances, knowledge of marine natural product biosynthesis metamorphosized during the last decade from a predominantly chemically-based perspective to now encompass the entirety of the Central Dogma, from transcription of DNA into RNA and translation into enzymes catalyzing chemical reactions essential in formation of marine natural products.
Dr John M Sanderson - Natural Product Biosynthesis
Piel et al. hypothesized that marine natural product biosynthesis followed genetic paradigms analogous to terrestrial actinomycetes and that the enterocins were derived from a type II polyketide synthase (PKS). Type II polyketide synthases are multi-enzyme complexes minimally consisting of two discreet ketosynthase units (KSα and KSβ) and an acyl carrier protein (ACP), which are employed iteratively in assembly of aromatic polyketides, as reviewed by Hertweck et al. Screening of a S. maritimus genomic DNA clone library for type II PKS-encoding gene sequences led to the identification and complete sequencing of the biosynthetic gene cluster for enterocins and wailupemycins (1–10, ). The function of this gene cluster was confirmed by heterologous expression of the pathway and further explored by a wide range of gene knockouts and enzymatic studies made possible by this complete gene sequence information.-