Expansion of Gamma-Butyrolactone Signaling Molecule Biosynthesis to Phosphotriester Natural Products.

Bacterial hormones, such as the iconic gamma-butyrolactone A-factor, are essential signaling molecules that regulate diverse physiological processes, including specialized metabolism. These low molecular weight compounds are common in species and display species-specific structural differences. Recently, unusual gamma-butyrolactone natural products called salinipostins were isolated from the marine actinomycete genus based on their antimalarial properties.

Cariogenic Produces Tetramic Acid Strain-Specific Antibiotics That Impair Commensal Colonization.

is a common constituent of dental plaque and a major etiologic agent of dental caries (tooth decay). In this study, we elucidated the biosynthetic pathway encoded by , a hybrid polyketide synthase and nonribosomal peptide synthetase (PKS/NRPS) biosynthetic gene cluster (BGC), present in a number of globally distributed strains. The natural products synthesized by included three -acyl tetramic acid compounds (reutericyclin and two novel analogues) and an unacylated tetramic acid (mutanocyclin).

Comparative Genomics of Cyanobacterial Symbionts Reveals Distinct, Specialized Metabolism in Tropical Sponges.

Marine sponges are recognized as valuable sources of bioactive metabolites and renowned as petri dishes of the sea, providing specialized niches for many symbiotic microorganisms. Sponges of the family are well documented to be chemically talented, often containing high levels of polyhalogenated compounds, terpenoids, peptides, and other classes of bioactive small molecules. This group of tropical sponges hosts a high abundance of an uncultured filamentous cyanobacterium, Here, we report the comparative genomic analyses of two phylogenetically distinct populations, which reveal shared deficiencies in essential pathways, hinting at possible reasons for their uncultivable status, as well as differing biosynthetic machinery for the production of specialized metabolites.

Total Enzyme Syntheses of Napyradiomycins A1 and B1.

The biosynthetic route to the napyradiomycin family of bacterial meroterpenoids has been fully described 32 years following their original isolation and 11 years after their gene cluster discovery. The antimicrobial and cytotoxic natural products napyradiomycins A1 and B1 are produced using three organic substrates (1,3,6,8-tetrahydroxynaphthalene, dimethylallyl pyrophosphate, and geranyl pyrophosphate), and catalysis via five enzymes: two aromatic prenyltransferases (NapT8 and T9); and three vanadium dependent haloperoxidase (VHPO) homologues (NapH1, H3, and H4). Building upon the previous characterization of NapH1, H3, and T8, we herein describe the initial (NapT9, H1) and final (NapH4) steps required for napyradiomycin construction.

Biosynthetic Pathway Connects Cryptic Ribosomally Synthesized Posttranslationally Modified Peptide Genes with Pyrroloquinoline Alkaloids.

In an era where natural product biosynthetic gene clusters can be rapidly identified from sequenced genomes, it is unusual for the biosynthesis of an entire natural product class to remain unknown. Yet, the genetic determinates for pyrroloquinoline alkaloid biosynthesis have remained obscure despite their abundance and deceptive structural simplicity. In this work, we have identified the biosynthetic gene cluster for ammosamides A-C, pyrroloquinoline alkaloids from Streptomyces sp.

d-3-Deoxy-dioctanoylphosphatidylinositol induces cytotoxicity in human MCF-7 breast cancer cells via a mechanism that involves downregulation of the D-type cyclin-retinoblastoma pathway.

Phosphatidylinositol analogs (PIAs) were originally designed to bind competitively to the Akt PH domain and prevent membrane translocation and activation. d-3-Deoxy-dioctanoylphosphatidylinositol (d-3-deoxy-diCPI), but not compounds with altered inositol stereochemistry (e.g.

Determination of noncovalent docking by infrared spectroscopy of cold gas-phase complexes.

Multidentate, noncovalent interactions between small molecules and biopolymer fragments are central to processes ranging from drug action to selective catalysis. We present a versatile and sensitive spectroscopic probe of functional groups engaged in hydrogen bonding in such contexts. This involves measurement of the frequency changes in specific covalent bonds upon complex formation, information drawn from otherwise transient complexes that have been extracted from solution and conformationally frozen near 10 kelvin in gas-phase clusters.

Oligo(N-alkoxy glycines): trans substantiating peptoid conformations.

Peptoid oligomers possess many desirable attributes bioactive peptidomimetic agents, including their ease of synthesis, chemical diversity, and capability for molecular recognition. Ongoing efforts to develop functional peptoids will necessitate improved capability for control of peptoid structure, particularly of the backbone amide conformation. We introduce alkoxyamines as a new reagent for solid phase peptoid synthesis.

Vibrational characterization of simple peptides using cryogenic infrared photodissociation of H2-tagged, mass-selected ions.

We present infrared photodissociation spectra of two protonated peptides that are cooled in a ~10 K quadrupole ion trap and "tagged" with weakly bound H(2) molecules. Spectra are recorded over the range of 600-4300 cm(-1) using a table-top laser source, and are shown to result from one-photon absorption events. This arrangement is demonstrated to recover sharp (Δν ~6 cm(-1)) transitions throughout the fingerprint region, despite the very high density of vibrational states in this energy range.

Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: enantioselective synthesis of D-myo-inositol-6-phosphate.

Despite the ubiquitous use of phosphoramidite chemistry in the synthesis of biophosphates, catalytic asymmetric phosphoramidite transfer remains largely unexplored for phosphate ester synthesis. We have discovered that a tetrazole-functionalized peptide, in the presence of 10-Å molecular sieves, functions as an enantioselective catalyst for phosphite transfer. This chemistry in turn has been used as the key step in a streamlined synthesis of myo-inositol-6-phosphate.

Catalyst-Dependent Syntheses of Phosphatidylinositol-5 Phosphate-DiC8 and its Enantiomer.

Peptide-based catalysts have been applied to the enantioselective syntheses of the title compounds, with this being the first report of the synthesis of an ent-PI5P analogue. The key steps in the synthesis involve asymmetric phosphorylation catalysis. Additional maneuvers were developed with a protecting groups scheme that enabled efficient, streamlined syntheses of these important mediators of biochemical events.

A dual role for integrin-linked kinase in platelets: regulating integrin function and alpha-granule secretion.

Integrin-linked kinase (ILK) has been implicated in the regulation of a range of fundamental biological processes such as cell survival, growth, differentiation, and adhesion. In platelets ILK associates with beta1- and beta3-containing integrins, which are of paramount importance for the function of platelets. Upon stimulation of platelets this association with the integrins is increased and ILK kinase activity is up-regulated, suggesting that ILK may be important for the coordination of platelet responses.

Extracellular disulfide exchange and the regulation of cellular function.

An emerging concept is that disulfide bonds can act as a dynamic scaffold to present mature proteins in different conformational and functional states on the cell surface. Two examples are the conversion of the receptor, integrin alphaIIbbeta3, from a low affinity to a high affinity state, and the interaction of CD4 receptor with the HIV-1 envelope glycoprotein gp120 to promote virus-cell fusion. In both of these cases there is a remodeling of the protein disulfide bonding pattern.

Mycobacterium avium subsp. paratuberculosis from free-ranging deer and rabbits surrounding Minnesota dairy herds.

The objectives of this study were to estimate the prevalence of Mycobacterium avium subsp. paratuberculosis (MAP) among deer and rabbits surrounding infected and noninfected Minnesota dairy farms using fecal culture, and to describe the frequency that farm management practices were used that could potentially lead to transmission of infection between these species. Fecal samples from cows and the cow environment were collected from 108 Minnesota dairy herds, and fecal pellets from free-ranging white-tailed deer and eastern cottontail rabbits were collected from locations surrounding 114 farms; all samples were tested using bacterial culture.

A role for the thiol isomerase protein ERP5 in platelet function.

Formation and rearrangement of disulfide bonds during the correct folding of nascent proteins is modulated by a family of enzymes known as thiol isomerases, which include protein disulfide isomerase (PDI), endoplasmic reticulum protein 5 (ERP5), and ERP57. Recent evidence supports an alternative role for this family of proteins on the surface of cells, where they are involved in receptor remodeling and recognition. In platelets, blocking PDI with inhibitory antibodies inhibits a number of platelet activation pathways, including aggregation, secretion, and fibrinogen binding.