Parallel analysis of transcript and metabolic profiles: a new approach in systems biology

The past few years in the medical and biological sciences have been characterized by the advent of systems biology. However, despite the well-known connectivity between the molecules described by transcriptomic, proteomic and metabolomic approaches, few studies have tried to correlate parameters across the various levels of systemic description. When comparing the discriminatory power of metabolic and RNA profiling to distinguish between different potato tuber systems, using the techniques described here suggests that metabolic profiling has a higher resolution than expression profiling. When applying pairwise transcript–metabolite correlation analyses, 571 of the 26,616 possible pairs showed significant correlation, most of which was novel and included several strong correlations to nutritionally important metabolites. We believe this approach to be of high potential value in the identification of candidate genes for modifying the metabolite content of biological systems

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

The rapid spread on multi-drug resistant strains of Staphylococcus aureus requires not just novel treatment options, but the development of faster methods for the identification of new hits for drug development. The exponentially increasing speed of computational methods makes a more extensive use in the early stages of drug discovery attractive if sufficient accuracy can be achieved. Computational target identification using systems-level methods suggested the histidine biosynthesis pathway as an attractive target against S. aureus. Potential inhibitors for the pathway were identified through docking, followed by ensemble rescoring that is sufficiently accurate to justify immediate testing of the identified compounds by whole cell assays, avoiding the need for time-consuming and often difficult intermediary enzyme assays. This novel strategy is demonstrated for three key enzymes of the S. aureus histidine biosynthesis pathway, which is predicted to be essential for bacterial biomass productions. Virtual screening of a library of ~10(6) compounds identified 49 potential inhibitors of three enzymes of this pathway. 18 representative compounds were directly tested on three S. aureus-and two E. coli strains in standard disc inhibition assays. 13 compounds are inhibitors of some or all of the S. aureus strains, while 14 compounds weakly inhibit growth in one or both E. coli strains. The high hit rate obtained from a fast virtual screen demonstrates the applicability of this novel strategy to the histidine biosynthesis pathway

DNA-damage-induced checkpoint pathways in the nematode Caenorhabditis elegans.

Genomic instability is believed to be an enabling characteristic of cancer (Hanahan and Weinberg 2000).Therefore, it is not surprising that sophisticated mechanisms exist to maintain the integrity of the genome. Damage to DNA triggers checkpoint controls that result in cellcycle arrest and repair of the lesion (Nurse 1997, 2000;Weinert 1998). In multicellular organisms, when DNAdamage is extensive, these potentially harmful cells areeliminated by apoptosis (Enoch and Norbury 1995; Evanand Littlewood 1998). Defects in communications between DNA damage and the apoptotic program leads tothe survival of cells with unstable genomes vulnerable tooncogene activation, ultimately leading to tumor development (Morgan and Kastan 1997; Orr-Weaver andWeinberg 1998; Hanahan and Weinberg 2000). Geneticwork in yeast has greatly improved our understanding ofthe molecular mechanisms of DNA-damage-inducedcheckpoint arrest and repair. On the other hand, DNAdamage-induced apoptosis cannot be studied in yeasts, asthe apoptotic program is missing in both Saccharomycescerevisiae and Schizosaccharomyces pombe (Fraser andJames 1998)..