Systemic Disease Associations with Disorders of Gut-Brain Interaction and Gastrointestinal Transit: A Review.

Functional gastrointestinal disorders (FGID) are now classified within the Rome IV framework as disorders of gut-brain interaction (DGBI). Disorders of gastrointestinal transit (as defined by abnormalities on contemporary gastrointestinal motility testing) frequently are associated with symptoms that are also characteristic of DGBIs. In this narrative review, we outline a non-inclusive set of systemic diseases or risk factors that have been classically associated with DGBIs and disorders of gastrointestinal transit; these include diabetes mellitus, paraneoplastic syndromes, surgery, Parkinson's disease, systemic sclerosis, endocrinopathies, polypharmacy, and post-infectious syndromes.

Liquid chromatography quadrupole time-of-flight mass spectrometry characterization of metabolites guided by the METLIN database.

Untargeted metabolomics provides a comprehensive platform for identifying metabolites whose levels are altered between two or more populations. By using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS), hundreds to thousands of peaks with a unique m/z ratio and retention time are routinely detected from most biological samples in an untargeted profiling experiment. Each peak, termed a metabolomic feature, can be characterized on the basis of its accurate mass, retention time and tandem mass spectral fragmentation pattern.

Mechanistic studies on CymD: a tryptophan reverse N-prenyltransferase.

The prenyltransferase CymD catalyzes the reverse N-prenylation of tryptophan using dimethylallyl diphosphate (DMAPP) in the biosynthesis of the cyclic peptides cyclomarin and cyclomarazine. The mechanism is of interest because a non-nucleophilic indole nitrogen must be alkylated in this process. Three mechanisms were initially considered, including (A) a direct addition of a carbocation to the nitrogen, (B) an addition of a carbocation to C-3 followed by an aza-Cope rearrangement, and (C) deprotonation of the indole followed by an S(N)2' addition to DMAPP.

Iron acquisition in the marine actinomycete genus Salinispora is controlled by the desferrioxamine family of siderophores.

Many bacteria produce siderophores for sequestration of growth-essential iron. Analysis of the Salinispora genomes suggests that these marine actinomycetes support multiple hydroxamate- and phenolate-type siderophore pathways. We isolated and characterized desferrioxamines (DFOs) B and E from all three recognized Salinispora species and linked their biosyntheses in S.

Significant natural product biosynthetic potential of actinorhizal symbionts of the genus frankia, as revealed by comparative genomic and proteomic analyses.

Bacteria of the genus Frankia are mycelium-forming actinomycetes that are found as nitrogen-fixing facultative symbionts of actinorhizal plants. Although soil-dwelling actinomycetes are well-known producers of bioactive compounds, the genus Frankia has largely gone uninvestigated for this potential. Bioinformatic analysis of the genome sequences of Frankia strains ACN14a, CcI3, and EAN1pec revealed an unexpected number of secondary metabolic biosynthesis gene clusters.

Functional characterization of the cyclomarin/cyclomarazine prenyltransferase CymD directs the biosynthesis of unnatural cyclic peptides.

In vitro and in vivo characterization of the cyclomarin/cyclomarazine prenyltransferase CymD revealed its ability to prenylate tryptophan prior to incorporation into both cyclic peptides by the nonribosomal peptide synthetase CymA. This knowledge was utilized to bioengineer novel derivatives of these marine bacterial natural products by providing synthetic N-alkyl tryptophans to a prenyltransferase-deficient mutant of Salinispora arenicola CNS-205.

Interpretation of tandem mass spectra obtained from cyclic nonribosomal peptides.

Natural and non-natural cyclic peptides are a crucial component in drug discovery programs because of their considerable pharmaceutical properties. Cyclosporin, microcystins, and nodularins are all notable pharmacologically important cyclic peptides. Because these biologically active peptides are often biosynthesized nonribosomally, they often contain nonstandard amino acids, thus increasing the complexity of the resulting tandem mass spectrometry data.

Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin.

Two new diketopiperazine dipeptides, cyclomarazines A and B, were isolated and characterized along with the new cyclic heptapeptide cyclomarin D from the marine bacterium Salinispora arenicola CNS-205. These structurally related cyclic peptides each contain modified amino acid residues, including derivatives of N-(1,1-dimethylallyl)-tryptophan and delta-hydroxyleucine, which are common in the di- and heptapeptide series. Stable isotope incorporation studies in Streptomyces sp.