Co-opting the bacterial lipoprotein pathway for the biosynthesis of lipidated macrocyclic peptides
Bibliographic record
Abstract
Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally diverse natural products that possess a range of bioactivities, often acting as antibiotics, antifungals, or metallophores. In RiPP biosynthesis, different modifying enzymes install an array of chemical motifs onto a precursor peptide. A recently described RiPP-modifying enzyme, ChrH, catalyzes a remarkably complex reaction on its precursor peptide that results in a macrocycle, heterocycle, and S- methyl group. By leveraging comparative genomics, we demonstrate that the products from a subfamily of enzymes related to ChrH display unexpected structural diversity, including the production of unmethylated macrocyclic congeners and C-terminally modified proteins over 30 kDa in size. Several of these precursors contain a signal peptide, sending them for downstream maturation by the bacterial lipoprotein biosynthetic pathway. Like bacterial lipoproteins, such peptides are modified by addition of a diacylglycerol (DAG) group to the N-terminal cysteine residue along with acylation of the N-terminal amine. Genome mining reveals that these RiPP-lipoprotein hybrids, which we term DAG-RiPPs, are widespread across bacterial phyla and are likely involved in different biological roles. Together, these results highlight a novel maturation paradigm for membrane-bound RiPPs and lay the foundation for the discovery and bioengineering of other RiPP-lipoprotein hybrids. Significance Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a superfamily of natural products that display antibiotic, antifungal, anticancer, and metal-binding activities. Their biosynthesis typically follows a common logic in which modifying enzymes install chemical motifs onto a precursor peptide, followed by proteolytic processing and export from the cell. Herein, we describe the discovery and biochemical characterization of a new class of lipid-RiPP hybrid products. These RiPPs contain a signal peptide that exploits the endogenous bacterial lipoprotein biosynthesis pathway for lipidation, membrane localization, and potential secretion. Genome mining shows that these lipid-peptide hybrids are widespread across bacterial phyla.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".