Journal Articles - UP - MSI
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- A conserved biosynthetic gene cluster is regulated by quorum sensing in a shipworm symbiontRobes, Jose Miguel D.; Altamia, Marvin A.; Murdock, Ethan G.; Concepcion, Gisela; Haygood, Margo G.; Puri, Aaron W. (American Society for Microbiology, 2022-06-14)Bacterial symbionts often provide critical functions for their hosts. For example, wood-boring bivalves called shipworms rely on cellulolytic endosymbionts for wood digestion. However, how the relationship between shipworms and their bacterial symbionts is formed and maintained remains unknown. Quorum sensing (QS) often plays an important role in regulating symbiotic relationships. We identified and characterized a QS system found in Teredinibacter sp. strain 2052S, a gill isolate of the wood-boring shipworm Bactronophorus cf. thoracites. We determined that 2052S produces the signal N-decanoyl-l-homoserine lactone (C10-HSL) and that this signal controls the activation of a biosynthetic gene cluster colocated in the symbiont genome that is conserved among all symbiotic Teredinibacter isolates. We subsequently identified extracellular metabolites associated with the QS regulon, including ones linked to the conserved biosynthetic gene cluster, using mass spectrometry-based molecular networking. Our results demonstrate that QS plays an important role in regulating secondary metabolism in this shipworm symbiont. This information provides a step toward deciphering the molecular details of the relationship between these symbionts and their hosts. Furthermore, because shipworm symbionts harbor vast yet underexplored biosynthetic potential, understanding how their secondary metabolism is regulated may aid future drug discovery efforts using these organisms.
- Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leadsRamiro, Iris Bea L.; Bjørn-Yoshimoto, Walden E.; Imperial, Julita S.; Gajewiak, Joanna; Salcedo, Paula Flórez; Watkins, Maren; Taylor, Dylan; Resager, William; Ueberheide, Beatrix; Bräuner-Osborne, Hans; Whitby, Frank G.; Hill, Christopher P.; Martin, Laurent F.; Patwardhan, Amol; Concepcion, Gisela; Olivera, Baldomero M.; Safavi-Hemami, Helena (American Association for the Advancement of Science, 2022-03-25)Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating a deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated a diverse set of SS analogs, each optimized to elicit specific systemic physiological effects in prey. The increased metabolic stability, distinct SS receptor activation profiles, and chemical diversity of the venom analogs make them suitable leads for therapeutic application, including pain, cancer, and endocrine disorders. Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.
- Transcriptomic profiling reveals extraordinary diversity of venom peptides in unexplored predatory gastropods of the genus ClavusLu, Aiping; Watkins, Maren; Li, Qing; Robinson, Samuel D.; Concepcion, Gisela; Yandell, Mark; Weng, Zhiping; Olivera, Baldomero M.; Safavi-Hemami, Helena; Fedosov, Alexander E. (Oxford University Press, 2020)Predatory gastropods of the superfamily Conoidea number over 12,000 living species. The evolutionary success of this lineage can be explained by the ability of conoideans to produce complex venoms for hunting, defense, and competitive interactions. Whereas venoms of cone snails (family Conidae) have become increasingly well studied, the venoms of most other conoidean lineages remain largely uncharacterized. In the present study, we present the venom gland transcriptomes of two species of the genus Clavus that belong to the family Drilliidae. Venom gland transcriptomes of two specimens of Clavus canalicularis and two specimens of Clavus davidgilmouri were analyzed, leading to the identification of a total of 1,176 putative venom peptide toxins (drillipeptides). Based on the combined evidence of secretion signal sequence identity, entire precursor similarity search (BLAST), and the orthology inference, putative Clavus toxins were assigned to 158 different gene families. The majority of identified transcripts comprise signal, pro-, mature peptide, and post-regions, with a typically short (<50 amino acids) and cysteine-rich mature peptide region. Thus, drillipeptides are structurally similar to conotoxins. However, convincing homology with known groups of Conus toxins was only detected for very few toxin families. Among these are Clavus counterparts of Conus venom insulins (drillinsulins), porins (drilliporins), and highly diversified lectins (drillilectins). The short size of most drillipeptides and structural similarity to conotoxins were unexpected, given that most related conoidean gastropod families (Terebridae and Turridae) possess longer mature peptide regions. Our findings indicate that, similar to conotoxins, drillipeptides may represent a valuable resource for future pharmacological exploration.
- Topoisomerase II-Mediated DNA cleavage by adocia- and xestoquinones from the Philippine sponge Xestospongia sp.Concepcion, Gisela; Foderaro, Tommaso A.; Eldredge, Glenn S.; Lobkovsky, Emil; Clardy, Jon; Barrows, Louis R.; Ireland, Chris M. (American Chemical Society (ACS), 1995-10)Investigation of an orange Xestospongia sp. sponge collected at Cape Bolinao in northern Luzon, Philippines, yielded the known compounds adociaquinones A and B (1, 2) and six new metabolites, secoadociaquinones A and B (3, 4), 14-methoxyxestoquinone (5), 15-methoxyxestoquinone (6), 15-chloro-14-hydroxyxestoquinone (7), and 14-chloro-15-hydroxyxestoquinone (8). All compounds showed inhibition of topoisomerase II in catalytic DNA unwinding and/or decatenation assays. Furthermore, adociaquinone B showed activity in a KSDS assay, suggesting it inhibits the enzyme by freezing the enzyme-DNA cleavable complex. Interestingly, adociaquinone B did not displace ethidium bromide from DNA or unwind supercoiled DNA, implying it does not intercalate DNA.
- On-resin synthesis of the somatostatin venom analog Consomatin Ro1de Boda, Ramoncito Luis; Acyatan, Zildjian; Concepcion, Gisela; Villaraza, Aaron Joseph (Philippine-American Academy of Science and Engineering, 2023-08-29)Consomatin Ro1 is a disulfide-containing peptide derived from the venom of the cone snail Conus rolani with a sequence that is similar to the vertebrate peptide hormone somatostatin. It has been shown to preferentially activate human somatostatin receptor subtypes 1 and 4, and to exhibit antinociceptive and antihyperalgesic properties making it an interesting peptide to study and develop as a chemical probe or an analgesic drug. Here, we describe the synthesis of Consomatin Ro1 using an onresin approach wherein the disulfide bond is formed while the peptide is still attached to the resin. This was achieved by selectively removing the methoxytrityl protecting group of Cys residues with a weak acidic mixture, and treating the resulting thiol-containing peptidyl resin with the mild oxidant Nchlorosuccinimide. The strategy yielded a considerably higher amount of the peptide when compared with the previously reported in-solution disulfide formation method.This work was funded by the Department of Science and Technology through Project 1. Anti-Pain and AntiNeurodegeneration Drug Candidates: Discovery and Development under the Discovery and Development of Health Products - Marine Component (Phase II) program. The authors would like to thank the Philippine Council for Health Research and Development for monitoring the research project.