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PubMed1992

Bioactive substances in nerve-cord extracts from an echiuroid, Urechis unicinctus--II. Peptidic substances.

1. Two peptides that showed an inhibitory effect on twitch contraction of the inner circular body-wall muscle of the echiuroid Urechis unicinctus were purified from extracts of the ventral nerve cords of the worms. 2. On the basis of the results of amino acid analysis, amino acid sequence analysis and FAB-MS measurement, the primary structures of the peptides were proposed to be H-Phe-Arg-Val-Phe-OH (FRVF) and H-Phe-Arg-Phe-OH (FRF). 3. FRVF and FRF were synthesized, and their behavior on HPLC and biological activities on the body-wall muscle were confirmed to be identical to those of the native peptides. 4. FRVF was also found to have a potentiating effect on spontaneous contractions of the intestine of the African clawed toad Xenopus laevis.

Amino Acid Sequence↗

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↗

PubMed1992

Patterns of prohormone processing. Order revealed by a new procholecystokinin-derived peptide.

An 83-amino acid cholecystokinin peptide with a sulfated tyrosine and an amidated carboxyl terminus (CCK-83) was purified from human intestinal mucosa. The purified peptide was chemically characterized, and its bioactivity was compared to CCK-8. Several post-translational processing steps such as cleavage at basic residues, sulfation, and amidation are necessary to form biologically active cholecystokinin from its nascent prepropeptide. The discovery of CCK-83 gives new insight into the order of preprohormone processing. The processing of prepro-CCK appears to be in the order of: 1) signal peptidase cleavage, 2) tyrosine sulfation, 3) cleavage after a carboxyl-terminal pair of basic residues, 4) carboxypeptidase B-like cleavage of these basic residues, 5) amidation (which results in the formation of CCK-83), and 6) cleavage at monobasic residues by endopeptidases (which results in the smaller molecular forms of cholecystokinin). The characterization of biologically active CCK-83 with a sulfated tyrosine and an amidated carboxyl terminus establishes the site of signal peptidase action and suggests an order of post-translational modifications that give rise to the various molecular forms of cholecystokinin.

Amino Acid Sequence↗

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↗

PubMed1992

Characterization of vascular neuropeptide Y receptors.

1. In the present study we compared neuropeptide Y (NPY) and NPY-related analogues for their ability to activate or bind to vascular NPY receptors in four experimental set-ups. Previous results have suggested the existence of different receptor subtypes, Y1 receptors requiring full-length NPY (1-36) or [Pro34]-NPY, and Y2 receptors recognizing also N-terminally truncated forms of NPY but not [Pro34]-NPY. 2. NPY 1-36 and [Pro34]-NPY dose-dependently increased arterial pressure in the anaesthetized rat with a similar magnitude and potency. NPY 2-36 was much less potent than NPY 1-36. NPY 4-36 and NPY 11-36 were inactive even at a dose as high as 10 nmol kg-1. 3. NPY 1-36, [Pro34]-NPY, NPY 2-36 and NPY 5-36 concentration-dependently increased the coronary resistance in the Langendorff preparation of the rat. NPY 1-36 and [Pro34]-NPY were equipotent, while NPY 2-36 and NPY 5-36 were about 7 and 20 times less potent. At 0.3 microM, NPY 11-36, NPY 20-36 and NPY 22-36 induced a slight contraction while NPY 23-36 was inactive. 4. NPY 1-36, [Pro34]-NPY, NPY 2-36, NPY 4-36, NPY 5-36 and NPY 11-36 evoked concentration-dependent contractions in the isolated inferior caval vein of the rat and guinea-pig. [Pro34]-NPY was more potent than NPY 1-36. NPY 2-36 was equipotent with NPY 1-36, while NPY 4-36, NPY 5-36 and NPY 11-36 were approximately 30 times less potent.5. [Pro34]-NPY was equipotent with NPY 1-36 in displacing the '25I-labelled gut hormone peptide([1251]-PYY) from rat aortic smooth muscle cells, while NPY 2-36 and shorter forms of NPY were much less potent or inactive.6. In caval vein smooth muscle cells of the rat, the displacement pattern was more complex than in aortic smooth muscle cells, in that both [Pro34]-NPY and NPY 13-36 effectively displaced the radioligand,albeit none of them completely.7. In conclusion, the NPY-evoked pressor response in the whole rat and coronary vessels seems to be mediated by vascular Y1 receptors and the binding characteristics of the NPY-related peptides in the aortic smooth muscle cells correspond to a population of such receptors. In the caval vein, the profile of the bioactivity and the binding affinity of the NPY-related peptides suggest a mixed population of Y1/Y2 receptors.

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↗

PubMed1992

Production and biological activity of hybrid growth hormone-releasing hormone propeptides.

Growth hormone-releasing hormone (GHRH), a hypothalamic hormone that stimulates the synthesis and release of growth hormone (GH) from anterior pituitary cells, has been previously produced by synthetic peptide chemistry and recombinant DNA procedures. GHRH is capable of stimulating growth as well as eliciting other anabolic effects on animals and thus may have potential applications in agriculture and human medicine. However, economical production of GHRH by recombinant DNA process has been difficult since GHRH is degraded rapidly by endogenous E. coli proteases. We report here an efficient process to produce hybrid GHRH analogs of higher molecular weight. These hybrid GHRH propeptides (proGHRH) are comprised of an analog of GHRH (44 aa) and the human GHRH carboxy-terminal peptide (33 aa). In E. coli K-12 RV308, the expression levels of the proGHRH analogs were estimated to be 10% of the total cellular protein. An in vitro assay to measure the release of rat growth hormone by GHRH analogs using crude E. coli lysates was also developed. This assay showed that the proGHRH analogs produced in E. coli efficiently stimulated GH release from rat anterior pituitary cells. One proGHRH analog, [alao]-proGHRH, was purified ans shown to efficiently elevate plasma GH levels in wether lambs. Our data indicate that the hybrid proGHRH peptides, unlike other hormone propeptides such as proinsulin, are remarkably bioactive.

Amino Acid Sequence↗

PubMed1992

Purification of cationic cystine-rich peptides from rat bone marrow. Primary structures and biological activity of the rat corticostatin family of peptides.

Seven cationic, cystine-rich peptides of 29 to 32 amino acid residues have been purified from extracts of rat bone marrow (R-1, R-1a, R-1b, R-2, R-3, R-4 and R-5). Structural analysis clearly indicated that all seven peptides belong to the corticostatin/defensin family of leukocyte-derived peptides known to participate in oxygen-independent killing of phagocytosed bacteria. For R-1 to R-5, six cysteine residues were found at characteristic and highly conserved positions. R-1a and R-1b were partially characterized and appear to be structural variants of R-1. Aside from the conserved cysteines, there is a remarkable degree of structural diversity evident within the sequences of those members of the corticostatin/defensin family characterized so far. The structures of the peptides that we have purified can be compared directly with the sequences obtained for rat defensins isolated from extracts of peritoneal neutrophils (Lehrer, Ganz and Selsted, Cell, 64 (1991) 229-230). Some discrepancies are apparent which can be explained in terms of proteolytic cleavage of several of these peptides at both amino- and carboxyl-termini. The corticostatins owe their bioactivity to their ability to compete with corticotropin for occupancy of the corticotropin receptor (Zhu, Hu, Mulay, Esch, Shimasaki and Solomon, Proc. Natl. Acad. Sci. USA, 85 (1988) 592-596). The potency of these peptides can be expressed in terms of their capacity to inhibit the steroidogenic response of isolated rat adrenocrotical cells half-maximally stimulated by corticotropin (i.e., at the ED50 concentration for corticotropin in this assay, namely 33 pM). In this assay, the rat peptides R-1, R-2 and R-3 were shown to be inactive. In contrast, the more cationic peptides R-4 and R-5 were found to inhibit steroidogenesis. R-4 was somewhat less active than rabbit corticostatin (IC50 25 nM) showing an IC50 value of 50 nM. R-5 appeared to be significantly less potent than R-4. The lower yield of R-5 precluded an accurate estimate of the corticostatic potency of this peptide. R-4 differs in structure from R-5 in having an arginine to serine substitution at position 7. It can be concluded that an arginine at this position accounts, at least in part, for the corticostatic activity of R-4.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

PubMed1992

A pharmacological comparison of parathyroid hormone receptors in human bone and kidney.

While abundant information is available characterizing PTH receptor properties in other species, data on human PTH receptors is very limited. We have been interested in the possibility that tissue-specific differences among human PTH receptors (i.e. bone vs. kidney) might exist. We have, therefore, compared pharmacological profiles for a wide array of PTH and PTH-related peptide (PTHrP) analogs in human osteoblast-like cells (SaOS-2) and human renal cortical membranes (RCM) using radioiodinated (Tyr36)hPTHrP(1-36)NH2 as a probe for PTH receptor function. The rank order of receptor affinity for 10 PTH/PTHrP receptor agonists tested was very similar in the bone and kidney assay systems. Binding affinity for these peptides was greater in human (h)RCMs and SaOS-2 membranes than in SaOS-2 intact cells. The relative binding affinities for (Tyr36)hPTHrP(1-36)amide, hPTH(1-34), bovine (b)PTH(1-34), and rat PTH(1-34) were similar in human RCMs, SaOS-2 membranes, and SaOS-2 cells. bPTH(1-84) and hPTHrP(1-74) both manifested lower receptor affinity than the amino-terminal analogs. Seven PTH/PTHrP receptor antagonists were also studied in this homologous human assay system. The binding affinity for hPTHrP(7-34)NH2 was 2- to 3-fold greater than that for (Tyr34)bPTH(7-34)NH2 in RCM and SaOS-2 membranes. However, in SaOS-2 cells, a striking reversal in the relative binding affinities was observed; the PTHrP(7-34) analog was nearly 3-fold less potent than (Tyr34)bPTH(7-34)NH2, underscoring a difference between intact and broken cell preparations. Two hybrid PTH-PTHrP receptor antagonists demonstrated similar relative affinity to each other in the human bone and kidney assay systems. Affinity cross-linking of receptors in human renal and skeletal tissues demonstrated an indistinguishable dominant 85-kilodalton receptor protein. We conclude that the binding and bioactivity profiles of a broad array of PTH and PTHrP peptides are very similar or identical in human renal and skeletal tissues. Differences relating to intact vs. broken cell preparations accounted for some variation in potency. These studies emphasize the importance of employing homologous assay systems to study PTH receptor function and the existence of interspecies differences among PTH receptors. The results support the possibility that PTH receptors in human bone and human kidney are very similar if not identical.

Affinity Labels↗

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↗

PubMed1992

Para-substituted Phe3 deltorphin analogues: enhanced selectivity of halogenated derivatives for delta opioid receptor sites.

The delta-selective opioid peptide deltorphin C(H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) (DEL C) was modified by para-substitution of Phe3 with halogens (F, Cl, Br, I), amino, or nitro groups. The bioactive potencies in peripheral tissues and brain receptor selectivities of these analogues depended upon the particular substituent; peptides containing halogen substituents exhibited the least disruptive effect. In the mouse vas deferens (MVD) bioassay, [p-ClPhe3]DEL C displayed equivalent bioactivities to DEL C; in combination with the guinea pig ileum (GPI) bioassay, [p-ClPhe3]DEL C and [p-BrPhe3]DEL C exhibited marked preference for delta sites (IC50GPI/IC50MVD = 11,250 and 6,363, respectively), which are approximately 4- and 2-fold greater than DEL C. In a receptor binding assay, none of the halogenated analogues had delta affinities (Ki) exceeding that of DEL C; however, in terms of delta selectivity (Ki mu/Ki delta), [p-BrPhe3]DEL C was nearly twice as selective as DEL C, while [p-FPhe3]DEL C was equivalent, and [p-IPhe3]DEL C only 25% less selective. The only correlation evident with the halogenated derivatives occurred between IC50GPI and Ki mu (r = 0.814) rather than between delta receptor studies (MVD or Ki delta); interestingly, IC50GPI also correlated with K' (r = 0.982). The p-amino or p-nitro substituents of Phe3 in DEL C and DEL B (= [Glu4]DEL C) were deleterious for bioactivity (MVD) (losses ranged from 400- to approximately 8,000-fold) and in receptor binding assays, where delta affinities decreased 140- to 840-fold and delta selectivities by 34- to 380-fold. p-Nitro-Phe3 was the most detrimental substitution for all the parameters measured for both deltorphins: the loss in MVD activity, however, was less with DEL B than with DEL C, which was the opposite for delta receptor affinity.

Amino Acid Sequence↗

PubMedDate not supplied

Synthetic amyloid beta-protein fails to produce specific neurotoxicity in monkey cerebral cortex.

Because progressive amyloid beta-protein (A beta P) deposition and surrounding neuritic dystrophy occur spontaneously in primates, we evaluated the in vivo effects of synthetic A beta P in monkey cortex. Experimental and control A beta P were stereotactically injected into multiple neocortical sites of adult rhesus monkeys in a vehicle of either artificial cerebrospinal fluid or acetonitrile. After 2 weeks or 3 months, injection sites were identified and characterized histologically and immunocytochemically. A beta P antibodies specifically detected the injected A beta P1-40 peptide. Serial sections stained with silver and antineurofilament protein demonstrated comparable degrees of degenerating neurons, dystrophic neurites, and axonal spheroids associated with both experimental and control peptide injections. Alz 50 staining was sparse or absent in all sites. We conclude that specific cellular changes closely resembling AD pathology were not detected in these experiments, and that control and experimental A beta P peptides produced indistinguishable effects. Methodological concerns regarding the in vivo modeling of A beta P bioactivity are discussed.

Amyloid beta-Peptides↗

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↗

PubMed1992

Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia?

The pathogenesis of extrapancreatic tumor hypoglycemia has been related to the secretion of big insulin-like growth factor (IGF) II by the tumor. In 25 of 28 patients with this type of hypoglycemia we found 1.5-8-fold elevated serum levels of immunoreactive big (15-25 kD), but decreased levels of normal IGF II. After removal of the tumor, big IGF II disappeared and normal IGF II increased. Tumors contained elevated levels of IGF II, 65-80% in the big form. The insulin-like bioactivity of big IGF II and its affinity towards IGF-binding proteins (IGFBP)-2 and -3 are similar to those of normal IGF II, but two- to threefold higher on a molar basis. Big IGF II is mainly bound to the 50-kD IGFBP complex. The latter contains approximately 10 times more of this peptide than in normal serum and displays three- to fourfold increased insulin-like bioactivity. The formation of the 150-kD IGFBP complex with 125I-recombinant human IGFBP-3 is impaired in tumor serum. This results in sequestration of IGFBP-3 and predominant association of big IGF II with IGFBP-2 and -3 in the 50-kD complex. Increased bioavailability of big IGF II in this complex due to unrestricted capillary passage and enhanced insulin bioactivity of this big IGF II pool provide a continuous increased insulin-like potential available to insulin and type 1 IGF receptors of insulin-sensitive tissues and thus may lead to sustained hypoglycemia.

Biological Availability↗

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↗