Abstract 2219 Exploring uncharted territory in RiPP biosynthesis: studies on curacozole, a cyanobactin from Streptomyces curacoi
Bibliographic record
Abstract
The majority of antibiotic, antiviral, and anticancer drugs used in modern medicine are natural products and their derivatives. Ribosomally synthesized and post translationally modified peptides (RiPPs) form a major class of bioactive natural products, comprising over 20 structurally distinct families. To unlock the full potential of RiPPs and opportunities for pathway engineering, we must develop a deeper understanding of their biosynthetic principles.1,2 The cyanobactins are a class of RiPP first discovered in cyanobacteria. They are small cyclic peptides that are highly modified through side chain cyclization, epimerization, prenylation, and oxidation.3 In recent years, similar compounds have been discovered in Streptomyces. This project aims to characterize the biosynthetic pathway of curacozole, a cyanobactin produced by the soil bacterium Streptomyces curacoi. A putative gene cluster has been proposed, but the functions of the many encoded enzymes are unknown as they share little similarity to the known biosynthetic gene clusters of cyanobactins, such as the patellamides and trunkamide.4,5 Enzymes and peptides were purified by nickel column chromatography. In vitro assays were performed and analyzed by LC-MS and MS/MS. So far, cyclodehydratase and dehydrogenase enzymes have been biochemically characterized by the formation of one heterocycle. Investigations of a putative Ile epimerase in the cluster show evidence of activity. Finally, a novel cupin-superfamily enzyme adjacent to the cluster shows oxidative activity and dependence on alpha-ketoglutarate. References 1. Hudson, G. A.; Mitchell, D. A. RiPP Antibiotics: Biosynthesis and Engineering Potential. Current Opinion in Microbiology 2018, 45, 61–69. 2. Montalbán-López, M.; Scott, T. A.; Ramesh, S.; Rahman et. al. New Developments in RiPP Discovery, Enzymology and Engineering. Nat. Prod. Rep. 2021, 38 (1), 130–239. 3. Sivonen, K.; Leikoski, N.; Fewer, D. P.; Jokela, J. Cyanobactins-Ribosomal Cyclic Peptides Produced by Cyanobacteria. Appl Microbiol Biotechnol 2010, 86 (5), 1213–1225. 4. Kaweewan, I.; Komaki, H.; Hemmi et. al. Isolation and Structure Determination of a New Cytotoxic Peptide, Curacozole, from Streptomyces Curacoi Based on Genome Mining. J Antibiot 2019, 72 (1), 1–7. 5. Schmidt, E. W.; Nelson, J. T.; Rasko et. al. Patellamide A and C Biosynthesis by a Microcin-like Pathway in Prochloron Didemni, the Cyanobacterial Symbiont of Lissoclinum Patella. Proc Natl Acad Sci U S A2005, 102 (20), 7315–7320. We would like to acknowledge NSERC for funding the research.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".