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At least 37 records · Page 2Linked to original sources

PubMed2025

Logical Exploration of Cinnamoyl-Containing Nonribosomal Peptides via Metabologenomic Targeting and Regulator Overexpression.

A targeted method for discovering cinnamoyl-containing nonribosomal peptides (CCNPs), a unique class of bioactive compounds, was devised by using cinnamoyl isomerase, a key enzyme in the biosynthesis of the cinnamoyl moiety, as a genome mining probe. A total of 39 hit strains were obtained, including 35 from polymerase chain reaction-based screening of the in-house bacterial library (2.5% of 1400 strains) targeting the cinnamoyl isomerase-encoding gene and 4 from the genome mining of online databases. Sequence similarity networking and phylogenetic analyses of the isomerase amplicons (∼530 bp) classified the CCNPs into three major substructure-based groups (Z-, E-, and M-type CCNPs) and revealed distinct clade-structure relationships (13 clades). To overcome the challenge of silent biosynthetic gene clusters, we activated these clusters by overexpressing conserved cluster-situated LuxR regulators combined with extensive culture optimization. CCNP production was metabolomically detected in the bacterial extracts by using the characteristic UV absorption and MS/MS fragments of cinnamoyl moieties. CCNP production was observed in 20 of the 39 hit strains, resulting in the isolation of 6 new CCNPs, including oxy-skyllamycin B (2), gwanacinnamycin (3), and luxocinnamycins A-D (4-7), with high structural novelty. Their structures were elucidated using comprehensive spectroscopic analyses and multiple-step chemical derivatizations, and the putative biosynthetic pathways were bioinformatically proposed. Gwanacinnamycin (3) exhibited significant antimycobacterial activity, whereas luxocinnamycin A (4) displayed moderate antiproliferative activity against stomach cancer cells. Our findings highlight a targeted metabologenomic approach combined with transcriptional regulator overexpression as a logical and efficient platform for the discovery of bioactive compounds from nature.

Peptides↗

PubMed1979

Biosynthesis of MSH and related peptides in the pars intermedia of the mouse: a pulse-chase analysis.

Protein biosynthesis in neurointermediate lobes of mouse pituitaries was investigated using pulse and pulse-chase techniques with [3H]lysine. Electrophoretic analysis of lobe homogenates on acid-urea gels resolved 11 labeled products. One was a large protein which was rapidly synthesized during pulse-incubations and disappeared during chase incubations. Three of the products increased during chase incubations, suggesting a precursor-product mode of biosynthesis for these chasde peptides. One of these three products co-migrated with synthetic alpha-MSH and also corresponds to the major peak of mouse neurointermediate lobe MSH bioactivity and immunoactivity on electrophoretograms. Another case of these peptides has electrophoretic properties similar to those of ACTH.

Animals↗

PubMed1979

Partial purification and characterization of a binding protein for insulin-like activity (ILAs) in human amniotic fluid: a possible inhibitor of insulin-like activity.

An insulin radioreceptor assay (INS-RRA) and an insulin-like activity radioreceptor assay (ILAs-RRA) have been utilized to partially purify and characterize a protein from human amniotic fluid with ILAs-RRA reactivity. An acid-ethanol soluble protein with an apparent molecular weight of 34,500 daltons by calibrated Sephadex chromatography and an isoelectric point (pI) of 4.7 accounts for all of the ILA'S-RRA reactivity present in human amniotic fluid. Since this protein has been found to be a binding protein for ILAs, but not insulin, it has been termed amniotic fluid binding protein or AFBP. AFBP is reactive in a non-parallel manner in the ILAs-RRA and totally inactive in the INS-RRA. The activity of AFBP in the ILAs-RRA is thus to the competition of AFBP with the placental membrane receptor for the [125I]ILAs tracer employed in the ILA'S-RRA. AFBP inhibits the activity of employed insulin, in the INS-RRA, presumably by binding ILAs, while being inactive itself. In two biological assays studied to date, the rat epididymal fat pad assay and the rabbit chondrocyte sulphation assay, AFBP also inhibits the activity of added ILAs. These observations raise the possibility that binding protein(s) for insulin-like peptides may function as inhibitors of their bioactivity in different physiologic and pathologic states. The relation of AFBP to binding protein(s) in human plasma remains to be clarified.

Amniotic Fluid↗

PubMed1979

Effect of transition metals on recovery from plasma of the growth-modulating tripeptide glycylhistidyllysine.

Isolation and purification of growth-modulating peptides from biological sources is often accompanied by excessive losses of bioactive material. During the isolation of a growth-modulating tripeptide glycylhistidyllysine (GHL) from human plasma, copper and iron were found to co-isolate with the peptide. Studies with [3H]GHL demonstrated that these metals interfere at several steps of the procedure for the isolation of GHL from plasma (gel filtration chromatography, high-pressure silica-gel). Removal of these metals with an insoluble chelating resin (Cellex 100) enhanced recovery of [3H]GHL from plasma 8-fold. These results suggest that removal of transition metals may aid in the recovery of peptides which are difficult to isolate from biological sources.

Chelating Agents↗

PubMed2026

Accessing Underexplored Biosynthetic Potential by Initiation Unit Engineering of Nonribosomal Peptide Synthetases in Proteobacteria.

Nonribosomal peptide synthetases (NRPSs) represent a valuable yet underexplored resource for producing bioactive natural products. However, most NRPSs remain silenced potentially due to factors such as dysfunction of the initiation unit. The starter condensation (Cs) domain of the initiation unit catalyzes the lipoinitiation of nonribosomal peptides via the incorporation of an N-terminal fatty acyl chain. The concept of initiation unit engineering introduced herein encompasses the replacement of the native initiation unit of NRPSs with a foreign and well-characterized Cs domain-containing initiation unit to activate the NRPS and optimize its expression. This strategy was employed herein to successfully access three of the six previously silent NRPS pathways in Mycetohabitans rhizoxinica HKI 454, a bacterium of the class β-proteobacteria, resulting in the identification of three classes of lipopeptides. This strategy was then extended to access two NRPS pathways in Pseudomonas syringae (γ-proteobacteria) and obtain novel lipopeptides, thereby establishing a feasible complement to existing genome mining strategies for natural product discovery. Furthermore, change of the initiation regions of biosynthetic pathways of nonlipidated chitinimide (β-proteobacteria) and pseudotetraivprolide (γ-proteobacteria) with heterologous Cs-containing initiation units enabled the successful incorporation of fatty acyl chains into the N-terminus of both peptide backbones, launching a workable approach to create artificial lipopeptides. Overall, this study provides a practical strategy for the rational recovery of silent BGCs and introduction of fatty acyl chains into nonribosomal peptides, at least in Proteobacteria, thereby enriching genome mining and combinatorial biosynthesis approaches for accessing the underexplored biosynthetic potential of NRPSs from various bacteria.

Proteobacteria↗

PubMed1975

Peptides with NH2-terminal tryptophan in adrenocorticotrophic hormone and melanocyte-stimulating hormone granules of adenohypophysis.

Fluorescence microscopy has demonstrated formaldehyde-ozone-induced fluorescence in the pars intermedia cells (melanocyte-stimulating hormone cells) and in certain cells of the pars distalis of the mammalian pituitary. From histochemical and chemical evidence the fluorescence is believed to reflect the presence of peptides with NH2-terminal tryptophan. In the pars distalis of hamster, cat and pig pituitary, the cells that exhibit formaldehyde-ozone-induced fluorescence have now been identified as adrenocorticotrophic hormone (ACTH) cells by immunohistochemistry. Granules from pig pituitaries were purified by passage through a succession of Millipore filters followed by centrifugation on a continuous sucrose gradient. Two granular fractions were identified by electron microscopy and found to contain high concentrations of peptides with NH2-terminal tryptophan as well as high ACTH bioactivity. These fractions, when pelleted and analyzed histochemically, displayed formaldehyde-ozone-induced fluorescence and ACTH-like immunoreactivity.

Adrenocorticotropic Hormone↗

PubMed2026

Genomic Insights Into Multidrug-Resistant Foodborne Serratia liquefaciens Strains Carrying mcr-9 and Comparative Genomic Analysis of Novel Biosynthetic Gene Clusters.

Serratia liquefaciens is an opportunistic nosocomial pathogen with a wide range of antibiotic resistance patterns. This study reports the characterization of the first mcr-9-positive S. liquefaciens strains, 35E-19E1 and CST-066, isolated from meat products in Japan. The strains were screened for the presence of β-lactamases, plasmid-mediated mobile colistin resistance (mcr) genes, and carbapenemase-encoding genes using PCR. Antimicrobial susceptibility was tested using the broth microdilution method. The strains exhibited multidrug resistance (MDR) phenotypes to third-generation cephalosporins, cephamycin, fosfomycin, and other clinically important antimicrobials. Genomic DNA sequencing showed that the genome sizes of CST-066 and 35E-19E1 are 5,529,704 and 5,261,506 bps, respectively. mcr-9 was identified on a chromosome within a genetic environment that included the two-component system qseBC, which plays a key role in the signaling network that triggers colistin resistance in Enterobacterales. Downstream genome analysis revealed a 1695-bp eptB-like kdo2-lipid phosphoethanolamine transferase, which is involved in intrinsic polymyxin resistance mechanisms in Serratia spp. The strain 35E-19E1 carries five CRISPR-Cas enzymes that are essential for adaptive immunity in bacteria, allowing defense against invading elements. Functional analysis using subsystem technology revealed that both strains possess subsystem features responsible for invasion and adhesion within the host biomes. Genome mining using antiSMASH and BAGL4 revealed various biosynthetic gene clusters, responsible for secondary metabolite synthesis. Notably, we identified novel gene clusters, mainly nonribosomal peptide synthetases, in both the strains, indicating their potential to produce bioactive compounds. Although the presence of mcr-9 in Serratia may not be of clinical significance because of natural resistance of the strain to polymyxins, we shed light on the genomic characteristics of this MDR pathogen and the potential spread of mcr-9 among other bacterial species. The emergence of mcr-9 in drug-resistant S. liquefaciens provides significant insights, underscoring the need for increased surveillance of this pathogen.

biosynthetic gene cluster↗

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

Marine-derived Bioactive Compounds: A Promising Frontier against Multidrug-resistant Microbial Infections.

The global escalation of Multidrug-Resistant (MDR) bacterial infections poses a serious and growing threat to public health, contributing to increased morbidity, mortality, and substantial economic burden worldwide. The widespread and often indiscriminate use of antibiotics in clinical and agricultural settings has accelerated the emergence of resistance, significantly diminishing the efficacy of conventional antimicrobial therapies. This pressing challenge necessitates the exploration of alternative sources for novel antibiotics. Marine ecosystems-renowned for their immense biodiversity and ecological complexity-have gained attention as a rich and largely untapped reservoir of bioactive natural products with potent antimicrobial activity. Marine organisms, such as sponges, tunicates, algae, and bacteria and fungi derived from marine sources, produce structurally diverse and pharmacologically active metabolites, including peptides, polyketides, alkaloids, terpenoids, sterols, lactones, and halogenated compounds. Many of these marine-derived molecules possess unique chemical scaffolds and novel mechanisms of action, offering the potential to circumvent existing resistance pathways. Some compounds have shown promising activity against MDR pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii. However, challenges such as low natural abundance, difficulty in cultivation, and structural complexity have limited their clinical translation. Recent advancements in marine biotechnology, genomics, metagenomics, and synthetic biology have opened new avenues for the discovery, biosynthesis, and structural optimization of these compounds. These innovative approaches not only facilitate sustainable production but also enhance the pharmacological properties.

Humans↗

PubMedDate not supplied

Metabolic activation of norethisterone (norethindrone) to an irreversibly protein-bound derivative by rat liver microsomes.

Norethisterone, specifically labeled with tritium, was incubated with hepatic microsomes of rats. About 2% of 3H radioactivity was irreversibly incorporated into the microsomal protein. This protein binding of norethisterone (about 0.7-1.6 nmol/mg of microsomal protein) was dependent on oxygen, NADPH, substrate concentration, and microsomal protein content and could be inhibited by carbon monoxide. Glutathione and other cysteine derivatives with free sulfhydryl groups diminished the microsomal protein binding diminished the microsomal protein binding as did the addition of bovine serum albumin. Norethisterone-derived radioactivity was also irreversibly bound to albumin. Solvent-extraction and charcoal-adsorption methods were employed to prove the irreversible nature of this binding. After trypsin digestion of albumin and microsomal protein loaded with norethisterone, peptides which were labeled with 3H could be isolated. To explain our results, a metabolic bioactivation of norethisterone to norethisterone-4,5-epoxide, catalyzed by the microsomal mixed-function oxidase cytochrome P-450, is proposed.

Adsorption↗

PubMed1978

Parathyroid hormone-like biological activity in urine.

1. The parathyroid hormone-like biological activity of concentrated urine was measured by the increase of plasma calcium concentration after intravenous injection of the sample into chickens. 2. Urine was tested in hypoparathyroid patients, normal volunteer subjects, primary hyperparathyroid patients before and after surgery and patients with secondary hyperparathyroidism. 3. In primary and secondary hyperparathyroidism the biological activity was significantly higher than in urine from normal subjects, which was in turn significantly higher than the activity in the urine of hypoparathyroid patients. This bioactivity diminished after surgical removal of a hyperparathyroid adenoma. 4. Decreased activity after trypsinization indicated the peptidic nature of the hypercalcaemic substance.

Animals↗

PubMed1975

Radioreceptor assay of insulin: Comparison of plasma and pancreatic insulins and proinsulins.

Porcine proinsulin, related intermediates and plasma immunoreactive insulin components have been studied by radioreceptor assay. Using the purified rat liver membrane or cultured human lymphocyte radioreceptor assay, porcine proinsulin is %5, split proinsulin 6% (54-55 split in connecting peptide) desdipeptide proinsulin 20% (deletion of amino acids 62 and 63 of connecting peptide) and desnonapeptide proinsulin 27% (deletion of amino acids 55-63 of connecting peptide) as active as porcine insulin in both assay systems; these values closely parallel the in vitro bioactivity of these preparations. In the lymphocyte radioreceptor assay the human plasma immunoreactive insulin-like component has the same potency as porcine insulin per immunoreactive unit, whereas the plasma immunoreactive proinsulin-like component is only 15% as active. Since both plasma immunoreactive components are somewhat less reactive than would be expected from puriified human insulin and proinsulin, the data suggest that both plasma components contain immunoreactive molecules that do not react in the radioreceptor assay.

Animals↗

PubMed1977

Adenylate cyclase of GH and ACTH producing tumors of human: activation by non-specific hormones and other bioactive substances.

The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE1 and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGE1 and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytroptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing's disease was stimulated by LH-RH, norepinephrine glucagon and MEE but not by TRH. Plasma levels of ACTH, beta-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE1 and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing's syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.

Acromegaly↗

PubMed2026

Protein isolation markedly enhances in vitro digestibility, nutritional quality, and bioactivity of fungal mycelial proteins.

Fungal mycelial proteins are promising sustainable protein sources, yet their nutritional utilization is often limited by structural constraints. This study systematically evaluated the effects of protein isolation on the proteomic composition, gastrointestinal digestion behavior, amino acid utilization, and bioactivity of Pleurotus citrinopileatus mycelial proteins. Quantitative proteomics identified 3591 proteins, of which 3374 were shared between mycelial flour (PCMF) and protein isolate (PCMPI), indicating that PCMPI primarily represents the soluble proteome fraction. In vitro digestion revealed that PCMPI exhibited significantly higher digestibility (93.98%) than PCMF (42.98%) (p < 0.05), reaching levels comparable to whey protein isolate. Enhanced enzymatic accessibility in PCMPI promoted rapid peptide generation during the gastric phase and efficient amino acid release during the intestinal phase, resulting in higher peptide (634.76 mg/g) and free amino acid levels (341.69 mg/g) at the digestion endpoint. Consequently, PCMPI achieved a balanced amino acid profile with a PDCAAS of 1.0. Moreover, its digestion products exhibited stronger antioxidant activity (IC₅₀ = 8.36 mg/mL) and ACE inhibitory activity (IC₅₀ = 15.65 mg/mL) compared with PCMF. Mechanistically, protein isolation disrupted the cell wall matrix, shifting digestion from a structure-limited to an accessibility-driven regime. Collectively, these findings demonstrate that protein isolation markedly enhances the digestibility, nutritional quality, and functional potential of mycelial proteins, supporting their application as high-value sustainable protein ingredients.

Digestion↗

PubMed2026

Large-scale discovery platform enables identification of peptides targeting drug-resistant candidiasis.

Natural products have an unparalleled track record as sources of clinical drugs. Among them, nonribosomal peptides (NRPs) stand as one of the most therapeutically significant classes, encompassing numerous approved anti-infective and anticancer agents. Yet, discovering bioactive NRPs remains profoundly challenging due to their complex biosynthesis and chemical architecture. Here, we present NPDiscover, a pathogen-oriented, scalable bioinformatics platform that integrates genome mining, metabolomics, and machine learning to identify NRPs active against drug-resistant pathogens. Applying NPDiscover to Actinobacteria datasets, we discovered edaphochelin A, a previously unreported NRP that kills multi-drug-resistant Candida auris and Candida glabrata by disrupting respiratory chain proteins. Structural elucidation via nuclear magnetic resonance and mass spectrometry, alongside in vitro and in vivo validation, confirmed its efficacy, safety, and a mode of action distinct from existing antifungals-establishing edaphochelin A as a compelling drug candidate and NPDiscover as a powerful engine for scalable natural product discovery.

CP: biotechnology↗

PubMed2025

Phyllosphere microbiomes in grassland plants harbor a vast reservoir of novel antimicrobial peptides and biosynthetic diversity.

INTRODUCTION: The phyllosphere microorganisms colonizing plant surface harbor capacities to synthesize diverse specialized metabolites that mediate communication and interactions with environment and host. However, most known metabolites are derived from a few culturable microorganisms, and the genomic diversity and biosynthetic potential of the vast majority of bacteria associated with plants remain largely unexplored. OBJECTIVES: Here, we aim to explore the genome architecture, biosynthetic ability, and host specific adaptability of grassland ecosystems, uncovering new perspectives on grassland phyllosphere microbial resources. METHODS: We employed ultra-deep metagenomic sequencing, functional analysis, host-associated characterization, and bioactivity assays to explore the phyllosphere microbiome across 221 grassland plant samples representing 45 families. This approach revealed host preference in biosynthetic gene clusters (BGCs) and validated the antimicrobial efficacy of phyllosphere-derived antimicrobial peptides (AMPs). RESULTS: Grassland plant phyllosphere microbiomes encode diverse BGCs. We identified 885,396 potential AMPs from over 68 million non-redundant gene sequences. Then, we reconstructed hundreds of near-complete genomes from phyllosphere metagenomes, and 32.61 % of reconstructed genomes were identified as unclassified genomes, primarily within Pseudomonadota, Actinomycetota, Bacillota and Bacteroidota phyla. Of the near-complete genomes, 91.97 % of the BGCs and 99.76 % of the identified AMPs were previously uncharacterized. Host phylogenetic analysis revealed functional divergence. Poaceae-associated Pseudomonas genomes contain an average of 28 BGCs, significantly higher than those in Asteraceae-associated genomes (mean = 14.76, P = 0.033). Similarly, Poaceae-associated Pantoea genomes carried an average of 9 BGCs, exhibiting significant enrichment compared to genomes from Asteraceae (mean = 7.13, P = 6.1e-05), Lamiaceae (mean = 7, P = 0.015), Ranunculaceae (mean = 8.22, P = 0.0053), and Rosaceae (mean = 7.75, P = 0.00069). ParaFit analyses further confirmed that host phylogeny significantly structures microbial functional repertoires, with intra-family hosts sharing more KEGG pathways than inter-family hosts. These results suggest that host evolutionary relationships are associated with metabolic specialization in phyllosphere microbiomes. All 13 AMPs synthesized via solid-phase peptide synthesis demonstrated antimicrobial activity, inhibiting the growth of at least one tested bacterial strain. CONCLUSION: This study demonstrates the promise of grassland plant phyllosphere microbiome as a rich source for novel antimicrobial agents.

Antimicrobial Peptides↗

PubMed1979

Secretin-like bioactivity in extracts of porcine brain.

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Animals↗

PubMed1976

Size heterogeneity of beta-MSH in ectopic ACTH-producing tumors: presence of beta-LPH-like peptide.

Gel chromatographic, immunologic and biologic properties of beta-melanocyte-stimulating hormone (beta-MSH) in tumor tissues obtained from eight patients with the ectopic ACTH syndrome were studied and compared to those of pituitary beta-MSH. Size heterogeneity of immunoreactive beta-MSH was found in all the tumors studied as well as in normal human pituitaries. Both the tumors and pituitaries contained immunoreactive beta-MSH of a larger molecular size than the well-characterized beta-MSH of small molecular size. The large molecular weight beta-MSH also predominated in the plasma. It was found to be bioactive by an in vitro MSH assay, immunologically indistinguishable from human beta-MSH, and chromatographically very similar to beta-lipotropic hormone (beta-LPH). Tryptic digestion of the large molecular weight beta-MSH under controlled conditions promptly produced bioactive beta-MSH of small molecular size, followed by the appearance of immunologically active but biologically inert fragments. These results suggest that the ectopic ACTH-producing tumor as well as the pituitary elaborate beta-LPH-like peptide which might be the predominant component of immunoreactive beta-MSH in man.

Adrenocorticotropic Hormone↗