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PubMed2026

Iterative Enoyl Reduction by a FabV-Family Enzyme Expands the Chemical Landscape of Discrete Polyketide Synthases.

Polyketides are a structurally diverse class of natural products with immense therapeutic potential. However, the biosynthetic output of discrete polyketide synthases (PKSs) has been constrained by a fundamental functional limitation: unlike modular Type I systems, discrete PKS systems typically lack integrated enoyl reductase (ER) activity. This constraint restricts their chemical repertoire primarily to unsaturated polyenes or aromatic scaffolds. Here, we characterize PbrC16, a FabV-family ER from a manumycin-type biosynthetic gene cluster (BGC) in Peterkaempfera bronchialis. This enzyme represents the first experimentally validated ER capable of functioning within discrete PKS architectures. In vitro biochemical reconstitution demonstrates that PbrC16 along with its homologue ScFabV catalyze iterative enoyl reductions in both β-ketoacyl-acyl carrier protein synthase III (KAS III)-dependent and highly reducing (HR) Type II PKS contexts, enabling the complete saturation of long-chain polyketide intermediates. Structural and computational analyses reveal the molecular basis for its exceptional substrate promiscuity and versatile acyl carrier protein (ACP) recognition. These findings resolve a long-standing "reductive gap" in discrete PKS biology and provide a "plug-and-play" module for the rational engineering of saturated polyketide scaffolds.

Polyketide Synthases↗

PubMed2025

Engineering Polyketide Stereocenters with Ketoreductase Domain Exchanges.

Polyketide synthases (PKSs) are versatile biosynthetic megasynthases capable of producing a diverse range of natural products with many applications, including in pharmaceuticals. The stereochemical precision of PKSs makes them a powerful tool for engineering tailored, unnatural polyketides; however, modifying the stereocenters of a PKS product while maintaining production levels remains a significant challenge. In this study, we systematically tested and evaluated strategies for ketoreductase (KR) domain exchanges, the domain responsible for setting stereocenters of polyketide products. After first optimizing the method for KR exchanges, we then performed 44 KR domain exchanges on three different PKSs to obtain high production of all four stereoisomers in vivo. By testing both one- and two-module PKS systems, we investigated how downstream modules process intermediates with altered stereochemistry and found that the configuration of the α-substituents was critical for gatekeeping by the ketosynthase (KS). To overcome this constraint, we investigated two different strategies for altering the KS domain, including introducing targeted mutations in the downstream KS, and exploring boundaries in exchanging the entire functional unit from the donor PKS. Both strategies successfully modified the KS stereocontrol with distinct trade-offs; the functional unit exchange resulted in higher titer improvements, though it was more likely to break the entire PKS. This study demonstrates a comprehensive approach to successfully engineering all four stereochemical configurations in multiple PKS systems, advancing our understanding of and ability to rationally modify polyketide stereochemistry through multiple engineering strategies.

Polyketides↗

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

Discovery of Glycosylated β-Amino Acid-Containing Macrolactams from Nonomuraea sp. 0L2P via Genome Mining.

β-Amino acid-containing macrolactams (β-AACMs) are a class of bioactive natural products characterized by nitrogen-containing starter units within polyketide-derived macrocycles. Here, we report four previously undescribed macrolactams, gruelactams A-D (1-4), from Nonomuraea sp. 0L2P, discovered through an integrated approach combining genome mining, 15N-labeling, and antibacterial screening. Their planar structures were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR and HRESI-MS, and their configurations were partially assigned based on ROESY data and bioinformatic analysis. Genome sequencing and antiSMASH analysis identified a putative type I polyketide synthase (PKS) biosynthetic gene cluster, enabling the proposal of a biosynthetic pathway. Bioactivity assays showed that gruelactam D (4) exhibits antibacterial activity against Bacillus cereus and Staphylococcus aureus, with MIC values of 8 and 16 μg/mL, respectively. These findings expand the chemical diversity of β-AACMs and demonstrate the utility of genome-guided approaches for discovering bioactive natural products from rare actinomycetes.

Anti-Bacterial Agents↗

PubMed2026

Integrated proteomic and acetylomic analyses reveal the metabolic reprogramming associated with increased tylosin-equivalent concentration in Streptomyces xinghaiensis sf106-B1.

Deciphering the metabolic basis of high-yield antibiotic production in Streptomyces is crucial for strain optimization. Atmospheric and room-temperature plasma (ARTP) mutagenesis of Streptomyces xinghaiensis sf106 generated a mutant with a 30% increase in tylosin-equivalent concentration (μg/mL). 4D-FastDIA quantitative proteomics identified 279 differentially abundant proteins enriched in the Type I polyketide synthase (PKS) pathway, with increased abundance of key macrolide-biosynthesis-related proteins. Lysine-acetylome profiling identified 1152 differentially abundant acetylation sites and revealed altered acetylation of enzymes involved in fatty acid metabolism and the tricarboxylic acid (TCA) cycle, suggesting adjustments in central metabolism associated with acyl-CoA precursor availability and energy generation. Integration of proteomic and acetylomic data suggests coordinated changes in protein abundance and lysine acetylation associated with the increased tylosin-equivalent concentration. These results highlight candidate nodes for rational metabolic engineering of S. xinghaiensis.

Streptomyces↗

PubMed2026

Efficient rDNA-mediated multi-copy integration of gene clusters in Aureobasidium melanogenum.

Aureobasidium melanogenum is a promising non-conventional yeast chassis for synthetic biology. However, techniques recombining large genetic fragments, such as gene clusters, are still unavailable, hindering further metabolic reprogramming in this chassis. To achieve multi-copy integration of genes, we employed highly repetitive ribosomal DNA (rDNA) sequences in A. melanogenum as homologous recombination sites for large genetic fragments. First, integration efficiency of three different regions of A. melanogenum rDNA were investigated: RNA polymerase I promoter region (rDNA1, 1.0 kb), partial 26S rDNA region (rDNA2, 1.0 kb), and RNA polymerase I terminator region (rDNA3, 1.0 kb). Our findings revealed that the highest copy numbers and expression stability were observed for the short heterologous green fluorescent protein gene (gfp, 0.7 kb) and the long native polyketide synthase gene (pks, 7.0 kb) after rDNA1-mediated integration. Specifically, the copy numbers reached 7.0 and 8.0 for gfp and pks, respectively, and they remained stably expressed in the genome after 120-h subculturing. Furthermore, an 11.0 kb gene cluster (comprising the native pks, phosphopantetheinyl transferase (npg1), and scytalone dehydratase genes (scd) responsible for melanin biosynthesis) was integrated at the rDNA1 site, resulting in stable recombination with 15.0 copies and an approximately 12-fold increase in melanin production. Overall, the convenience and efficiency of the proposed rDNA-mediated multi-copy insertion strategy will facilitate superior metabolic engineering of A. melanogenum chassis cells.

Multigene Family↗

PubMed2026

Biosynthesis and Glycosylation of Antarlides, the Polyene Macrolides Possessing Androgen Receptor Antagonistic Activity.

Antarlides (ATLs) are tetraene macrolides discovered from Streptomyces spp. They demonstrated excellent antagonist activities toward mutated androgen receptors (ARs) related to the drug resistances in AR-targeted prostate cancer treatment. Herein, a biosynthetic gene cluster (BGC) of type I modular polyketide synthases (PKSs) from S. conglobatus ATCC 31005 was verified to be responsible for the biosynthesis of ATLs in the heterologous host S. lividans SBT5. The atl BGC was also activated in situ in S. conglobatus by equipping a strong promoter for the PKS genes operon. Unexpectedly, a new glycosylated product, ATL D1, was produced in the heterologous expression. ATL D1 was also generated in the S. conglobatus mutant bearing activated atl BGC through the introduction of a GT1 family glycosyltransferase gene mgt from S. lividans. Enzymatic analysis showed that the protein MGT catalyzed the glycosylation of ATL D to yield ATL D1 by attaching a β-d-glucose to the C11-hydroxyl position. Moreover, site-directed mutation of MGT resulted in an iterative glycosylation to yield ATL D2 bearing a disaccharide at the C11-hydroxyl. These results offer a platform for constructing efficient biosynthetic pathway of ATLs, and the O-glycosylation could be applied to improve the pharmaceutical properties of ATLs.

Glycosylation↗

PubMed2026

Genomic signatures of host-range divergence in the generalist Beauveria bassiana and the specialist Beauveria brongniartii.

Entomopathogenic fungi of the genus Beauveria are widely used biological control agents that infect diverse insect hosts and can also associate with plants as rhizosphere colonizers and endophytes. Within this genus, Beauveria bassiana is a cosmopolitan generalist, whereas Beauveria brongniartii exhibits a narrower host range, primarily targeting soil-dwelling coleopteran larvae with limited evidence of plant colonization. To explore genomic differentiation associated with this ecological divergence, the commercially exploited B. brongniartii strain BIPESCO2 and B. bassiana ATHUM 4946 were sequenced using Oxford Nanopore technology, followed by comparative genomic analyses across multiple strains. Orthology identified species-specific gene families, although overall genome architecture and core gene content were highly conserved. The CAZyme repertoires were nearly identical, indicating retention of a versatile enzymatic toolkit supporting plant association, saprotrophy, and insect pathogenicity. In contrast, biosynthetic gene clusters displayed substantial variation, including structural remodeling of Beauveria-specific virulence-associated clusters and expansion of type I polyketide synthase clusters in B. brongniartii. Effector prediction revealed a conserved core of largely uncharacterized proteins alongside species-specific orthogroups enriched in adhesion-, immunity-, and cuticle-interaction domains. Together, these findings indicate that host-range divergence in Beauveria is associated with compartmentalized genomic differentiation, particularly in secondary metabolism and a limited subset of lineage-specific virulence factors, rather than in the conserved core infection machinery.

Beauveria↗

PubMed2026

Genome mining reveals an architecturally expanded pyoluteorin-associated biosynthetic gene cluster and a divergent flavin-dependent halogenase-like sequence in deep-sea Pseudomonas Aeruginosa from the Gulf of Guinea.

BACKGROUND: Marine deep-sea environments harbour microorganisms with extraordinary biosynthetic potential, yet their secondary metabolite repertoires remain largely uncharacterised. RESULTS: This study reports the isolation, phenotypic characterisation, and whole-genome analysis of Pseudomonas aeruginosa strain E1, recovered from deep Atlantic seawater (Gulf of Guinea, ~2500 m depth), which exhibits antifungal activity against multidrug-resistant Candida parapsilosis. Three presumptive P. aeruginosa isolates (E1, E17, and E44) showed > 99% 16S rRNA gene sequence identity to P. aeruginosa reference sequences, while whole-genome dDDH analysis of strain E1 yielded 95.2% (95% CI: 93.6-96.4%; formula d4) relative to the P. aeruginosa type strain DSM 50071ᵀ (= ATCC 10145ᵀ), supporting its species-level assignment. Antifungal screening and PCR-based detection of flavin-dependent halogenase genes identified strain E1 as the primary candidate for genomic investigation. Illumina whole-genome sequencing produced a 6.33 Mb draft genome assembly (113 contigs, 5862 protein-coding genes, 66.4% GC content). Genome mining with antiSMASH 8.0 identified 27 biosynthetic gene clusters (BGCs) spanning nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS), phenazine, terpene, and metallophore pathways. Region 7.1 of strain E1 harbours a predicted 50.8 kb pyoluteorin-associated BGC, comprising 34 genes, substantially larger than its terrestrial counterpart (~ 22 kb, ~ 17 genes), and featuring nine transport genes and three regulatory elements. Phylogenetic analysis resolved three halogenase genes: ctg7_146 showed 98.7% amino acid identity to PltA, and ctg7_149 showed 99.2% amino acid identity to PltM, supporting their annotation as PltA-like and PltM-like components of the predicted pyoluteorin biosynthetic pathway. Among the characterised reference enzymes included in this analysis, ctg7_143 showed the highest amino acid identity to PltM from P. fluorescens Pf-5. However, the identity remained low at approximately 30.4%, supporting its placement as a divergent FDH-like sequence rather than a close PltM orthologue. CONCLUSION: This study provides the first comprehensive genomic characterisation of a pyoluteorin-BGC-harbouring marine P. aeruginosa strain, demonstrating conservation of the core biosynthetic machinery alongside an expanded transport architecture and a divergent FDH-like sequence that may represent a candidate for future biochemical investigation. These findings expand current knowledge of FDH-like sequence diversity in deep-sea bacteria and support further investigation of Gulf of Guinea microorganisms as a potential source of biosynthetic and enzymatic diversity.

Multigene Family↗

PubMed2026

Genomic analysis of regulatory mechanisms governing EPS66A biosynthesis in Streptomyces changanensis HL-66.

Streptomyces changanensis HL-66 produces the α-(1,4)/(1,6)-glucan exopolysaccharide EPS66A, a potent plant immune elicitor with promising applications in plant protection. However, its low native fermentation yield limits large-scale application. To investigate the biosynthetic potential and regulatory mechanisms underlying EPS66A production, the whole genome of HL-66 was sequenced and analyzed. The HL-66 genome is 6.82 Mb in size, with a GC content of 74%, and encodes 6081 predicted functional genes. Among these, 1390 genes were annotated to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, 4187 were assigned to Gene Ontology (GO) terms, and 143 were classified into Clusters of Orthologous Groups (COG) categories. antiSMASH analysis identified 22 secondary metabolite biosynthetic gene clusters, including multiple polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) clusters. Functional analyses revealed that the glycosyltransferase gene (GTy) and the global regulatory gene (bldD) are involved in EPS66A biosynthesis. bldD is involved in morphological development and EPS66A production, whereas GTy specifically regulates EPS66A production without affecting growth or development. In both in vivo and potted-plant experiments, EPS66A (200 μg/mL) significantly reduced the severity of tobacco mosaic virus, apple anthracnose leaf spot, walnut bacterial leaf spot, and jujube anthracnose, achieving control efficacies of 90.21%, 87.95%, 77.41%, and 68.55%, respectively, and outperforming a commercial chitosan oligosaccharide control. These findings provide new insights into the genetic architecture and regulatory mechanisms of EPS66A biosynthesis and support its development as a polysaccharide-based green pesticide.

Streptomyces↗

PubMed2026

Complete genome sequence of Streptomyces californicus ADR1, an anti-infective, anti-biofilm and anti-oxidant producing endophyte isolated from the medicinal plant Datura metel.

OBJECTIVE: Streptomyces californicus strain ADR1 is an endophytic actinobacterium isolated from Datura metel that produces secondary metabolites with potent antibacterial and anti-biofilm activities against WHO-listed high-priority Gram-positive pathogens. While anti-bacterial and antioxidant potential of the strain ADR1 has been extensively characterized, its complete genome sequence remains to be investigated for further insights into its biosynthetic potential. This study presents the complete genome sequence analysis of the strain ADR1 to provide a robust genomic foundation for understanding its metabolic versatility and biosynthesis of compounds with therapeutic significance. DATA DESCRIPTION: The ADR1 genome was sequenced using Illumina HiSeq. The assembly comprised 262 scaffolds with a total genome size of 8.4 Mb and G + C content of 72.5%, containing 7427 protein-coding genes. AntiSMASH and IIT-Hyderabad novelBGC analysis revealed 39 biosynthetic gene clusters, including non-ribosomal peptide synthetases, type I polyketide synthases, terpene and melanin clusters, correlating with the diverse therapeutic compounds previously identified through GC-MS analysis. This high-quality genome provides crucial insights into the biosynthetic potential underlying potent antimicrobial and antioxidant activities of the strain ADR1.

Streptomyces↗

PubMed2026

Mechanisms linking the gut microbiota to colorectal cancer development and progression.

Colorectal cancer remains a leading cause of global cancer mortality, with a concerning rise in early-onset cases driven by complex interactions between environmental exposures, lifestyle factors, and host genetics. Mounting evidence indicates that gut microbiota dysbiosis critically modulates this oncogenic process, acting as an active participant rather than a passive bystander. This review systematically synthesizes the dichotomous roles of the intestinal microbiome in colorectal tumorigenesis through the conceptual framework of the driver-passenger model. We discuss how early initiating driver bacteria, such as Polyketide synthase-positive Escherichia coli and enterotoxigenic Bacteroides fragilis, compromise mucosal barriers, induce chronic mucosal inflammation, and inflict direct genomic instability. As the local tumor microenvironment undergoes profound metabolic remodeling, opportunistic passenger pathogens, notably Fusobacterium nucleatum, become enriched, further promoting cellular proliferation and facilitating tumor immune evasion. Conversely, protective commensals, exemplified by Clostridium butyricum and Streptococcus thermophilus, exert robust tumor-suppressive effects through multifaceted mechanisms. These beneficial microbes actively antagonize malignant progression by redirecting tumor metabolic fluxes toward oxidative stress, orchestrating deep epigenetic reprogramming, and degrading core oncoproteins to reverse chemoresistance. Transitioning from fundamental mechanisms to clinical application, we evaluate a comprehensive spectrum of microbiota-targeted interventions, encompassing non-invasive diagnostic biomarkers, fecal microbiota transplantation, engineered bacteria, phage therapy, and postbiotics. Finally, we critically address the formidable translational challenges associated with microbial heterogeneity, long-term safety, and regulatory standardization, aiming to provide a balanced perspective on integrating microbiome-based strategies into next-generation precision oncology for colorectal cancer.

Humans↗

PubMed2026

A Wagner-Meerwein-Like Rearrangement Generates a Vinyl Group in the Biosynthesis of the Polychlorinated Lipopeptides Fischerazoles.

The discovery of structurally unusual natural products is a major inspiration in the search for novel enzymatic transformations. In this study, we employ stable isotope-labeled precursor feeding and metabolomics to reveal highly unusual cyanobacterial lipopeptides-fischerazoles A-C. These metabolites contain a polychlorinated fatty acyl-derived moiety with a vinyl branch and an N-methylated carboxamide-thiazole terminus. Most strikingly, stable-isotope-labeled precursor supplementation showed that during fischerazole biosynthesis, a linear, hexadecanoic acid-derived intermediate is processed to yield the ultimately branched alkyl moiety. The branched carbon becomes part of the vinyl group together with an S-adenosyl methionine (SAM)-derived carbon. A candidate polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) fischerazoles biosynthetic gene cluster-fsh-was identified in the genome of the producing strain, Fischerella sp. PCC 9431. In vitro assays experimentally connected fsh genes to fischerazole biosynthesis and revealed that the SAM-dependent methyltransferase FshF catalyzes a Wagner-Meerwein-like rearrangement to generate the vinyl group from an ACP-tethered unsaturated fatty acid. The discovery of FshF, which is related to the well-characterized cyclopropane fatty acid synthases (CFASs), brings to light a new biocatalytic strategy for alkyl chain functionalization.

Lipopeptides↗