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PubMed2026

Analysis of the genome of a Pseudomonas monsensis isolate that produces the antifungal dipeptide maculosin.

Candida species have been attributed to causing ~647,000 deaths annually. Candida albicans has been identified by the WHO as a priority pathogen for targeted antifungal drug development. To this end, we have screened microbial strains from the public outreach project Swab and Send for anti-Candida activity. This process identified Pseudomonas sp. SS1954.14, which displayed potent activity against C. albicans, both on agar and in a cell-free supernatant assay. Whole-genome sequence analysis identified this strain as Pseudomonas monsensis. It contains several biosynthetic gene clusters, suggesting that it can produce hydrogen cyanide, lokisin, pyoverdine and colicin/carocin, which may contribute to the observed antifungal activity. However, an active compound was separated by preparative high-performance liquid chromatography and identified through high-resolution mass spectrometry as maculosin [cyclo(Pro-Tyr)]. This cyclic dipeptide has previously been found to possess antifungal activity, but the exact biosynthetic mechanism remains undetermined. Reporting this genome alongside the associated evidence of maculosin production represents a valuable resource for biosynthetic investigations.

Candida albicans↗

PubMed2026

The proteomic origin of the genetic code.

INTRODUCTION: The origin and evolution of the genetic code is a central problem in molecular biology. Classical models have emphasized stereochemistry, frozen accidents, or adaptive optimization, often treating proteins as passive products of preexisting codes. More recent views instead portray the code as a dynamic, coevolving system shaped by reciprocal interactions among amino acids, RNA, and early catalysts. AREAS COVERED: Here, I review efforts of phylogeny reconstruction of the history of tRNA, protein structural domains, and dipeptide sequences in proteomes. These complementary approaches allow exploration of the entry of amino acids and codons into the code, and the transition from an operational RNA code in the tRNA acceptor arm to the canonical code in the anticodon loop. Evidence for ancestral synthetase enzymes with dual functions in aminoacylation and peptide-bond formation, as well as early bidirectional (sense-antisense) coding reflected in dipeptide-antidipeptide emergence is also discussed. EXPERT OPINION: The genetic code is best viewed as a proteome-driven, evolvable system in which early peptides actively shaped coding rules by stabilizing structure, expanding chemical diversity, and enhancing catalysis. This perspective connects origin-of-life studies with modern efforts of code expansion, translational engineering, and peptide-based therapeutics, highlighting the impact of the code's proteomic origin.

Genetic Code↗

PubMed2026

Deciphering the Function and Structure of PA1216 as an S-Adenosyl-l-Methionine Binding Protein Using Differential Scanning Fluorimetry and Circular Dichroism.

Microbes produce bioactive secondary metabolites as toxins, pigments, or virulence factors. These specialized compounds are produced by nonribosomal peptide synthetases (NRPS), polyketide synthases (PKS), or hybrid NRPS/PKS pathways. The genes encoding NRPS and PKS reside in biosynthetic gene clusters (BGCs), some of which have no identified metabolite associated with them. Characterization of these orphan BGCs could provide insights into potential bioactive compounds that have yet to be discovered. Here, we characterize PA1216, a putative methyltransferase embedded within an NRPS BGC in Pseudomonas aeruginosa strain PAO1. We cloned, expressed, and purified PA1216, and developed an optimized differential scanning fluorimetry assay to measure its thermal stability, demonstrating concentration-dependent stabilization in the presence of established methyltransferase cofactors and inhibitors. We then adapted this assay for high-throughput screening of potential PA1216 substrates, identifying destabilizing compounds, including glycyl-glycine dipeptides, amino esters with aromatic or basic side chains, and N-Boc-protected amino acids. In contrast, sodium salts of organic acids stabilized PA1216. Lastly, we employed AlphaFold to construct a predictive model, revealing that PA1216 contains a Rossmann-like fold and a glycine-rich loop, typical of class I methyltransferases, and we corroborated these secondary structural elements using circular dichroism spectroscopy. Overall, these studies illuminate PA1216 function and establish a platform for characterizing cryptic gene clusters within secondary metabolic pathways.

Circular Dichroism↗

PubMed2026

Establishment of human induced pluripotent stem cell lines and isogenic gene-corrected controls from three patients with prolidase deficiency.

Prolidase deficiency is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the PEPD gene. To date, close to 200 patients have been reported worldwide with a poorly understood pathomechanism. The PEPD gene encodes an enzyme that is involved in the final steps of collagen degradation. Urine amino acid analysis or specific dipeptide analysis can establish the biochemical diagnosis. In this study, we reprogrammed peripheral blood mononuclear cells (PBMCs) from three prolidase deficient patients into induced pluripotent stem cell (iPSC) lines and additionally generated isogenic controls using CRISPR-Cas9 genome editing. The pathogenic PEPD variants identified in our patients were NP_000276.2:p.? (NIHTVBi032-A), NP_000276.2:p.(Ile415Asn)/NP_000276.2:p.(Trp326Ter) (NIHTVBi033-A), and NP_000276.2:p.(Arg265Ter) (NIHTVBi034-A). These iPSC lines are valuable models to help investigate the pathomechanism of prolidase deficiency.

Humans↗

PubMed2026

Multi-dimensional profiling of primary metabolites in Heuchera micrantha varieties reveals potential for functional food development.

Heuchera micrantha is a horticultural plant with emerging pharmacological value, yet its primary metabolites remain underexplored. This study comprehensively profiled nutrient metabolites in four H. micrantha varieties using LC-MS/MS. We identified 285 metabolites, with amino acid derivatives being predominant. Multivariate analysis revealed distinct varietal accumulation patterns and 204 differential accumulated metabolites (DAMs). Integrative network pharmacology and molecular docking suggested γ-glutamyltyrosine and L-prolyl-L-phenylalanine as potential bioactive dipeptides that may interact with core hubs (MAPK1, EGFR, SRC) involved in cancer and inflammation pathways, though these predictions require experimental validation. Transcriptomics identified 39 differentially expressed genes regulating the biosynthesis of their precursor amino acids. Antioxidant assays showed varietal differences: some excelled in free radical scavenging (DPPH/ABTS) while others demonstrated superior reducing power (FRAP). This multi-omics study suggests that H. micrantha may be a rich source of therapeutically relevant primary metabolites, providing a preliminary scientific basis for its development as a functional food or nutraceutical pending further validation.

Functional Food↗

PubMed2026

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

Animals↗

PubMed2025

The Biosynthetic Pathway to the Pyrroloiminoquinone Marine Natural Product Ammosamide C.

Ammosamide C is a marine natural product containing a highly decorated pyrroloiminoquinone core. Studies on the biosynthetic gene cluster (BGC) that produces ammosamides previously revealed that they are made by a series of posttranslational modifications (PTMs). The BGC includes genes encoding a precursor peptide AmmA and four enzymes known as PEptide Aminoacyl-tRNA Ligases (PEARLs). Initial studies into the ammosamide biosynthetic pathway demonstrated Trp addition to a precursor peptide by the PEARL AmmB2. Thereafter, sequential modifications by several enzymes, including two other PEARLs lead to the formation of a peptide intermediate bearing a C-terminal diaminoquinone. In the present work, we present the biosynthetic steps that convert this intermediate to ammosamide C. The PEARL AmmB4 unexpectedly appends an arginine to the C-terminus of the aforementioned intermediate. Then, C-terminal proteolysis by the heterodimeric TldD/E-like protease Amm12/13 releases a dipeptide, which is subsequently cleaved by the dipeptidase Amm19 to produce a Trp-derived diaminoquinone. Amm3 next catalyzes the conversion of this Trp derivative to the corresponding chlorinated ammosamaic acid. Finally, a putative aminotransferase Amm20 performs an amidation, and Amm23 methylates this intermediate to arrive at ammosamide C; the order of these last two steps could not be determined definitively. This study reveals an unexpectedly lengthy route to ammosamide that illustrates the opportunistic nature of natural product biosynthesis, demonstrates a role for a PEARL that is unlike previous roles, identifies steps that are not PTMs, and adds Arg-tRNA to the growing repertoire of aminoacyl tRNAs that are used by PEARLs.

Biological Products↗

PubMed2026

Integrated computational and experimental benchmarking of Bacillus phage endolysins reveals the relationship between peptidoglycan-fragment recognition descriptors and antibacterial performance.

Protein-based antibacterials such as bacteriophage endolysins offer a targeted therapeutic strategy against Gram-positive pathogens. However, prioritizing the most effective candidates from the large sequence diversity available remains a significant challenge. Here we present a standardized computational-experimental benchmarking framework that evaluates seven phage-derived endolysin variants (E1, E2, E3, E7, E10, E12, and E15) identified from Bacillus genomes. We combined molecular docking and residue-level interaction mapping against muramyl dipeptide (MDP), a minimal conserved peptidoglycan motif, with 1000-ns molecular dynamics simulations, MM/PBSA binding free-energy estimation, and matched functional inhibition assays against Staphylococcus aureus and Micrococcus luteus. Computational analyses revealed generally favorable MDP recognition across variants, albeit with notable differences in contact patterns and complex stability profiles. Experimental screening identified E2 as the most potent antibacterial agent against both species, while E7 and E1 performed strongly in selected computational metrics. Integrated analysis showed only modest correlations between computational descriptors of fragment recognition/stability and observed antibacterial performance. This study establishes a practical comparative benchmarking platform for endolysin candidate prioritization, nominates E2 and E7 as promising candidates for further development, and highlights E1 as a potential structural scaffold for rational engineering, while explicitly demonstrating both the utility and the current limitations of using minimal peptidoglycan fragments as proxies for full cell-wall recognition in lysin benchmarking.

Endopeptidases↗

PubMed2026

Micropeptides encoded by lncRNAs associated with cancer progression reveal novel immunogenic epitopes.

MOTIVATION: Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Recent studies indicate that ∼20% of the ∼36 000 human lncRNA genes harbor small open reading frames (sORFs) capable of producing micropeptides (MPs), whose functions remain largely unknown. Whether these peptides contribute to the cancer immunopeptidome is largely unexplored. RESULTS: We systematically analyzed lncRNAs with strong experimental and computational evidence of MP-encoding potential (∼13% of the initial MP collection). Using The Cancer Genome Atlas (TCGA), we identified 2606 high-confidence lncRNA-derived MPs encoded by 647 genes across 16 cancer types. We then focused on 501 MPs from 124 lncRNA genes whose expression changes significantly across tumor stages and metastatic transitions, representing cancer transitional lncRNAs (Tr-lncRNAs). Dipeptide composition and conservation analyses showed that these MPs differ from a size-matched human coding proteome, supporting their potential as neoantigens. All possible 9-mer peptides were evaluated for predicted binding to prevalent European HLA class I alleles. Approximately 60% of Tr-lncRNA genes and 184 (37%) of derived peptides exhibited strong predicted HLA binding. Peptides from XIST, PCAT7, PVT1, HAND2-AS1 showed broad HLA coverage. Notably, TTN-AS1, encoded an MP (79 aa) generated 33 predicted distinct epitopes spanning all 27 HLA alleles. Our analysis identifies lncRNA-derived MPs as a previously underexplored source of potential cancer neoantigens, highlighting their promise as biomarkers and targets for immunotherapy. AVAILABILITY: Data, code and supplementary materials are available in https://doi.org/10.5281/zenodo.20167452 and GitHub: https://github.com/stavzok1/lncrna_peptide_analysis.

Humans↗

PubMed2026

Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.

Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.

Neurons↗

PubMed2025

Generation of C9orf72 repeat knock-in iPSC lines for modelling ALS and FTD.

Induced pluripotent stem cell (iPSC) models are powerful tools for neurodegenerative disease modelling, as they allow mechanistic studies in a human genetic environment and they can be differentiated into a range of neuronal and non-neuronal cells. However, these models come with inherent challenges due to line-to-line and clonal variability. To combat this issue, the iPSC Neurodegenerative Disease Initiative (iNDI) has generated an iPSC repository using a single clonal reference line, KOLF2.1J, into which disease-causing mutations and revertants are introduced via gene editing. Here we describe the generation and validation of lines carrying the most common causative mutation for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a repeat expansion in the C9orf72 gene, for the iNDI collection of neurodegenerative iPSC models. We demonstrate that these C9orf72 knock-in lines differentiate efficiently into neurons and display characteristic C9orf72-associated pathologies, including reduced C9orf72 levels and the presence of dipeptide repeat proteins (DPRs) and RNA foci, which increase in abundance over time in culture. These pathologies are not present in revertant cells lacking the repeat expansion. These repeat expansion and revertant cell lines are now available to academic and for-profit institutions through the JAX iPS cell repository and will help to facilitate and standardise iPSC-based ALS/FTD research.

Journal Article↗

PubMed2026

Prognostic value of circulating tumor DNA and copy-number alterations in patients receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 therapy for metastatic castration-resistant prostate cancer: a prospective observational study.

BACKGROUND: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) demonstrates clinical efficacy in metastatic castration-resistant prostate cancer (mCRPC), yet robust biomarkers for dynamic treatment monitoring and resistance remain lacking. We investigated circulating tumor DNA (ctDNA)-derived tumor fraction (TFx) and genome-wide copy-number alterations (CNAs) as non-invasive biomarkers of treatment response and resistance biology. METHODS: Seventy-eight patients with advanced mCRPC receiving tandem [225Ac]Ac-/[177Lu]Lu-PSMA-617 were prospectively enrolled. Plasma samples collected longitudinally (n = 172) underwent ultra-low-pass whole-genome sequencing. TFx was estimated using ichorCNA, and recurrent CNAs were identified using GISTIC2.0. Associations with progression and overall survival (OS) were assessed using Cox proportional hazards models, including time-dependent analyses. RESULTS: Baseline TFx differed across metastatic disease stages (p = 0.027) and dynamic TFx changes paralleled PSA kinetics during early treatment. Modelled as a time-dependent variable, TFx was associated with a significantly increased risk of progression (HR 4.9, 95% CI 1.2-20.1, p = 0.026). Unsupervised clustering identified distinct high- and low-CNA burden groups strongly correlated with TFx (p = 8.09 × 10⁻8). High CNA burden was associated with shorter median OS (8.3 vs 13.8 months). Multivariable analysis identified baseline logPSA and logALP as independent predictors of OS. Recurrent CNAs affected key tumor suppressors (PTEN, RB1, BRCA2, ATM) and were enriched in pathways related to TP53 signalling, homologous recombination repair, and oncogenic signaling. Longitudinal analyses demonstrated persistence and expansion of specific amplifications at progression. CONCLUSIONS: ctDNA-derived TFx represents a dynamic biomarker of treatment response and progression risk, while CNA profiling provides insight into resistance mechanisms in mCRPC treated with PSMA-RLT. These findings support the integration of ctDNA-based biomarkers into clinical stratification and real-time monitoring strategies.

Humans↗