The genome project of Plasmodium falciparum has been completed and other plasmodia species are on the line. The stage-dependent transcription has also been completed. The challenge of organizing the annotated gene products into functional meaning is the purpose of the website.
The Plasmodium genome contains genes that are expressed during specific stages of the parasite cycle, while other genes may be expressed throughout the entire cycle in the vertebrate host and the mosquito vector. Many gene-encoded proteins are essentially enzymes that participate in various biological functions. Deploying those processes in a useful format may facilitate not only the placement of expressed proteins in the functional context, but also to portray the various co-factors and metabolites that are involved in the activity of each enzyme. The essential advantage of this website is that it is manually curated and continuously updated as new data emerge in the literature.
The metabolic pathways of Plasmodium were extracted from the Kyoto University Encyclopedia of Genes and Genomes site (KEGG) that provides the common consent views of biochemistry that are not specific to particular organisms. Each enzyme is linked to the biochemical databases BRENDA (http://www.brenda-enzymes.org), ExPASy ENZYME (http://www.expasy.org/enzyme/) and to KEGG compounds (http://www.genome.jp/dbget-bin/www_bfind?compound), to provide supplementary information. The entries are also linked to PlasmoDB (http://plasmodb.org/) alowing direct access to annotated or predicted gene. In cases where specific inhibitors were demonstrated to be active against the parasite, they are depicted next to the process that they affect linked to the relevant literature. The site is constructed in a hierarchical pattern that permits logical deepening:
Each map is linked to other maps thus enabling to verify the origin of a substrate or the fate of a product. In maps of metabolic pathways, clicking on the EC number that appears next to each enzyme connects the site to BRENDA, ExPASy ENZYME, and PlasmoDB, thus providing:
While in these sites, a wealth of additional information can be obtained, such as chemical information, including an interactive view of the structure. Several other sites can be then directly accessed, such as PROSITE that supplies biochemical information on the enzymatic reaction and sequence of the catalytic domain; BRENDA that provides a wealth of information about the enzymatic activity, pH and temperature dependence, kinetic parameters (Km, turnover number), cofactors, effect of metal ions and a list of inhibitors. Each of these details is annotated with the relevant literature. While inside PlasmoDB, all the tools available in this database are available for deeper scrutiny.
Clicking of the name of a metabolite, connects the site to KEGG thus providing its chemical structure and formula as well as every mchemical reaction in which the compound may be participating through different enzymes (http://www.genome.jp/dbget-bin/www_bfind?enzyme).
Next to each enzyme there is a pie that depicts the stage-dependent transcription of the enzyme's coding gene. The pie is constructed as a clock of the 48 hours of the parasite cycle, where red signifies over-transcription and green, under-transcription.
A vast amount of data is provided in table format, e.g., phosphorylated proteins, post-translationally modified proteins, etc. Each entry is tagged by its PfID which allows its connection to the other elements of the DB.
A loop icon next to a map component indicates that information is available on its sub-cellular location. Pressing on the component name or the EC number opens a menu from which the pictures can be accessed. All existing pictures were collected from the literature and are present with a legend and a link to the original article.
The drug database of MPMP consists of antiplasmodials that target specific enzymes or metabolic pathways. These were and are currently collected and linked to their relevant targets. However, many papers are published that report antiplasmodial activities of synthetic compounds or of compounds that are derived from traditional medicine that have no known target. MPMP thought that it would be useful to include both these classes of compounds in the website. In most cases the report includes many compounds, sometimes, dozens of them, either for SAR analysis or because they all are present in the plant extract. For practical reasons only the most active compound is shown in the DB. The list of compounds can be searched by drug name, year of publication or name of article. The list also contains reviews that can similarly be searched.
Each map is connected to PubMed with a search string that uses all items that appear on the map. The result is a typical PubMed output that allows for direct retrieval of the publications abstract (when available).
The site contains a search engine that allows for searching enzymes by their names (including all synonyms) or EC numbers, other proteins and metabolites by their names or IDs. Pressing on search in the main menu opens the search facility. Choosing an item by browsing the list and pressing the “SEARCH” button, or typing the EC number in the designated windows and pressing the “SEARCH” button, will invoke the map(s) where this item appears. Combined searches can be done through Map Analysis. Thus, you can ask "which are the enzymes of the glycolysis pathway that are also phosphorylated".
The site contains a detailed tutorial that allows mastering of the site's intricacies and details.
The information for the construction of the metabolic maps has been collected by Prof. Hagai Ginsburg who also designed the maps and keeps them updated. Construction of the website portal with all links and search tools and the construction of the underlying DB were done by Alex Artyomov and Ofir Bar Lev.
The Computation Authority of The Hebrew University of Jerusalem, Israel provides the space for this site on its server. The construction of this site received financial support form the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the National Institute of Allergy and Infectious Diseases (NIAID) through its MR4, the BioMalPar Network of Excellence on Biology and Pathology of the Malaria Parasite and by European Virtual Institute of Malaria Research/European Network of Excellence. Present funding is from private money of HG.