Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein-protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.

Mixed sequence DNA can exist in two right-handed and one left-handed double helical conformations--A, B and Z. Under conditions of high water activity the B conformation prevails. If the water activity is reduced on addition of salt or organic solvents, transformation occurs to A-DNA or, in DNAs with alternating purine-pyrimidine sequences, to the left-handed Z-DNA. In crystal structure analyses of oligonucleotides, the free oxygen atoms of adjacent phosphate groups along the polynucleotide chain in B-DNA are found at least 6.6 A apart and individually hydrated whereas they are as close as 5.3 A in A-DNA and 4.4 A in Z-DNA, and bridged by water molecules. We suggest that this more economical hydration in A- and Z-DNA compared with B-DNA is the underlying cause of B----A and B----Z transitions.

The recently discovered non-mevalonate biosynthetic route to isoprenoid precursors is an essential metabolic pathway in plants, apicomplexan parasites, and many species of bacteria. The pathway relies on eight enzymes exploiting different cofactors and metal ions. Structural and mechanistic data now exist for most components of the pathway though there remain some gaps in our knowledge. The individual enzymes represent new, validated targets for broad spectrum antimicrobial drug and herbicide development. Detailed knowledge of the pathway may also be exploited to genetically modify microorganisms and plants to produce compounds of agricultural and medical interest. Isopentenyl pyrophosphate (IPP)2 and dimethylallyl pyrophosphate (DMAPP) are the universal precursors of natural products called isoprenoids. This large family, in excess of 35,000 distinct compounds, includes molecules such as sterols, dolichols, triterpenes, ubiquinone, components of macromolecules such as prenyl groups, and isopentenylated tRNAs (1-3). The diverse chemical properties of isoprenoids are exploited in varied and important biological functions including electron transport, hormone-based signaling, the regulation of transcription and post-translational processes, meiosis, apoptosis, glycoprotein biosynthesis, and protein degradation. In addition, isoprenoids are structural components of cell and organelle membranes.Two biosynthetic routes to IPP and DMAPP have evolved. For many years it was assumed that the mevalonate (MVA) pathway was the sole route to IPP and DMAPP. This pathway uses seven enzymes to supply the precursors in most eukaryotes (all mammals), archaea, a few eubacteria, the cytosol and mitochondria of plants, fungi, and Trypanosoma and Leishmania (4). This pathway starts with production of acetoacetyl-CoA from two molecules of acetyl-CoA in a reaction catalyzed by thiolase. A third acetyl-CoA is then condensed with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase. The NADPH-dependent HMG-CoA reductase then converts the CoA derivative to (R)-MVA. Next, in ATP-dependent steps, (R)-MVA is phosphorylated to (R)-MVA 5-diphosphate sequentially by mevalonate kinase and diphosphomevalonate kinase. The diphosphate is subsequently decarboxylated by mevalonate diphosphate decarboxylase to yield a pool of IPP. An IPP isomerase then produces DMAPP from some of the IPP. A wealth of data are available on the constituents of the MVA pathway in large part because of its relevance for human health. The MVA pathway leads to the biosynthesis of cholesterol, and inhibition of HMG-CoA reductase by statins controls production of the sterol with benefits for lowering blood pressure, the treatment of cardiovascular disease, and inflammatory processes (5).The mevalonate-independent pathway was discovered only recently (6 -8). This pathway is called the non-mevalonate route or alternatively, the 1-deoxy-D-xylulose-5-phosphate (DOXP) or 2C-methyl-D-erythritol-4-phosphate (MEP) pathway. This pathway occurs in plant ...

The structure of the TR-trypanothione enzyme-substrate complex provides details of a potentially valuable drug target. This information has helped to identify a new class of enzyme inhibitors as novel lead compounds worthy of further development in the search for improved medicines to treat a range of parasitic infections.