Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica

Abstract

Recent fermentation studies have identified actinomycetes of the marine-dwelling genus Salinispora as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp S. tropica CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that S. tropica dedicates a large percentage of its genome (Ϸ9.9%) to natural product assembly, which is greater than previous Streptomyces genome sequences as well as other natural product-producing actinomycetes. The S. tropica genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in Streptomyces species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive slm loci. This study firmly establishes the genus Salinispora as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.genome mining ͉ marine bacteria ͉ natural products ͉ polyketide synthase

Mining the Cinnabaramide Biosynthetic Pathway to Generate Novel Proteasome Inhibitors

“…[21][22][23] The C-terminal domains of CinA and CinB form the terminal NRPS module of the assembly line, and the highly homologous domain set in the salinosporamide gene cluster is known to activate the nonproteinogenic amino acid b-hydroxy-2'-cyclohexenylalanine. [12,24] Because of the structural similarity of the two compounds, and because the deduced substrate specificity code of the CinB A domain (DLMNVGGV; determined as described previously [25,26] ) showed a significant degree of similarity to that of the SalB A domain (DLLSNGGV), we propose elongation of the cinnabaramide intermediate by extension with b-hydroxy-2'-cyclohexenylalanine (Scheme 2 B). The resulting PCP-tethered cinnabaramide intermediate is then thought to undergo an intramolecular condensation promoted by the ketosynthase (CinC) to generate the g-lactam ring, which provides the CinB-bound alcohol substrate that gives rise to the offloaded b-lactone product.…”

A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis

“…1) or a 10-membered ring such as CAL and dynemicin (4)(5)(6). To date, there are 11 enediynes that have been structurally elucidated (4, 7) with several more potential enediynes in existence, including two marine-derived compounds hypothesized to originate as enediynes and to undergo aromatization upon isolation (8,9) and several structurally uncharacterized enediynes that have been predicted based on conserved and apparently cryptic genetic information (10)(11)(12).…”

The Crystal Structure of the Adenylation Enzyme VinN Reveals a Unique β-Amino Acid Recognition Mechanism

“…In many cases, adenylation enzymes that activate ␤-amino acids are involved in their biosynthetic pathways (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Similar to ␣-amino acid-activating enzymes, the interaction with the ␤-amino group and the carboxylate group should be important for ␤-amino acid-activating enzymes to fix the substrate orientation.…”