Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by 1 H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e., low circulating levels of plasma phosphatidylcholine and high urinary excretion of methylamines (dimethylamine, trimethylamine, and trimethylamine-Noxide), coprocessed by symbiotic gut microbiota and mammalian enzyme systems. Conversion of choline into methylamines by microbiota in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD. These data also indicate that gut microbiota may play an active role in the development of insulin resistance.metabonomics ͉ NMR ͉ nonalcoholic fatty liver disease ͉ nutritional genomics ͉ metabolic syndrome H ighly complex animals such as mammals can be considered as ''superorganisms'' with a karyome, a chondriome, and a microbiome (1), resulting from a coevolutionary symbiotic ecosystem of diverse intestinal microbiota interacting metabolically with the host (2). Recent molecular analyses of human microbiota 16s ribosomal DNA sequences revealed a majority of uncultivated or unknown species with a strong degree of interindividual diversity (3, 4). Also, some of the molecular foundations of beneficial symbiotic host-bacteria relationships in the gut were revealed by colonization of germ-free mice with known microbes and by comparisons of the genomes of members of the intestinal microbiota (5). For instance, Bacteroides thetaiotaomicron, a dominant member of normal distal intestinal microbiota, hydrolyzes otherwise indigestible dietary polysaccharides, thus supplying the host with 10-15% of calorific requirement (6). Gut Lactobacillus spp. are also responsible for a significant proportion of bile acid deconjugation, a process that efficiently reduces lipid absorption in the gut (7). Such symbiotic relationships are the result of coevolution and operate at the genome, proteome, and metabolome levels (6,8).Insulin resistance (IR) is central to a cluster of frequent and increasingly prevalent pathologies, including type 2 diabetes mellitus, central obesity, hypertension hepatic steatosis, and dyslipidemia (9). IR contributes to major causes of morbidity and mortality worldwide (10). Epidemiological and genetic studies in human and animal models have demonstrated the importance of both genetic and environmental factors in the etiology of IR (9): Dietary variation and intervention, in particular, have a strong influence on the development of IR. Nonalcoholic fatty liver disease (NAFLD), is the most frequent liver condition associated with IR (11). It is associa...

Bedbugs (Cimex lectularius or Cimex hemipterus) are cosmopolite hematophagus insects, and recent outbreaks have been reported in all major occidental countries. Although they are suspected of transmitting more than 40 infectious agents, no report has yet definitively demonstrated that capacity.

No abstract

Two genes involved in the biosynthesis of the depsipeptide antibiotics pristinamycins I (PI) produced by Streptomyces pristinaespiralis were cloned and sequenced. The 1.7-kb snbA gene encodes a 3-hydroxypicolinic acid:AMP ligase, and the 7.7-kb snbC gene encodes PI synthetase 2, responsible for incorporating L-threonine and L-aminobutyric acid in the PI macrocycle. snbA and snbC, which encode the two first structural enzymes of PI synthesis, are not contiguous. Both genes are located in PI-specific transcriptional units, as disruption of one gene or the other led to PI-deficient strains producing normal levels of the polyunsaturated macrolactone antibiotic pristinamycin II, also produced by S. pristinaespiralis. Analysis of the deduced amino acid sequences showed that the SnbA protein is a member of the adenylate-forming enzyme superfamily and that the SnbC protein contains two amino acid-incorporating modules and a C-terminal epimerization domain. A model for the initiation of PI synthesis analogous to the established model of initiation of fatty acid synthesis is proposed.Pristinamycins I (PI), cyclohexadepsipeptide antibiotics produced by Streptomyces pristinaespiralis, are members of the streptogramin B group. They are coproduced with the polyunsaturated macrolactone antibiotics pristinamycins II (PII), members of the streptogramin A group (6, 52). Like many other small metabolites with a peptide structure, PI are synthesized nonribosomally by large multifunctional enzymes (49). More than 25 years ago, Lipmann emphasized the analogy between nonribosomal peptide synthesis and fatty acid synthesis (25). In his model, large multifunctional enzymes called peptide synthetases (PPSs) catalyze elongation of a peptide covalently linked to a phosphopantetheinyl arm by a thioester bond (for a review, see reference 23). The original version of the thiotemplate multienzymatic mechanism was revised recently, and a multiple-carrier model was proposed (39,43,46,53). According to this model, each amino acid is activated as an aminoacyl adenylate and linked to the enzyme as a thioester with a phosphopantetheinyl group. Elongation then occurs by transfer of the activated carboxyl to the amino group of the next amino acid, thus effecting N-to-C stepwise condensation. Primary structure analysis of several PPS genes resulted in the identification of approximately 1,000-aminoacid (aa)-long modules selectively catalyzing activation and condensation of one amino or hydroxy acid (30, 51). The modules are organized such that they are colinear with the sequence of the oligopeptide. Each module can be subdivided in domains. The activation domain (500 aa) belongs to the large family of adenylate-forming enzymes that includes firefly luciferase and acyl coenzyme A (acyl-CoA) synthetases and contains nine core sequences (named boxes A to I by Pfeifer et al.

SummaryFour pap genes (papA, papB, papC, papM ) were found by sequencing near to snbA, a Streptomyces pristinaespiralis gene which was previously shown to encode one of the pristinamycin I (PI) synthetases. Analysis of the homologies observed from the deduced amino acid sequences suggested that these four genes could be involved in the biosynthesis of the PI precursor 4-dimethylamino-L-phenylalanine (DMPAPA). This was first verified when disruption of papA in S. pristinaespiralis led to a PI ¹ phenotype, which was reversed by the addition of DMPAPA into the culture medium. Further confirmation was obtained when papM was overexpressed in Escherichia coli and the corresponding protein purified to homogeneity. It catalysed the two successive N-methylation steps of 4-amino-L-phenylalanine leading to DMPAPA via 4-methylamino-L-phenylalanine. These results allowed us to assign a function to each of the four pap genes and to propose a biosynthetic pathway for DMPAPA.