Abstract
LIGAND is a composite database comprising three sections: ENZYME for the information of enzyme molecules and enzymatic reactions, COMPOUND for the information of metabolites and other chemical compounds, and REACTION for the collection of substrate–product relations. The current release includes 3390 enzymes, 5645 compounds and 5207 reactions. The database is indispensable for the reconstruction of metabolic pathways in the completely sequenced organisms. The LIGAND database can be accessed through the WWW (http://www.genome.ad.jp/dbget/ligand.html ) or may be downloaded by anonymous FTP (ftp://kegg.genome.ad.jp/molecules/ligand/ ).
INTRODUCTION
Recent progress in the transcriptome and proteome analyses has made it possible to examine expression data of whole mRNAs or proteins in a cell and also a large amount of protein–protein interaction data. The information on gene expression and protein interactions is indispensable to predict gene functions from the complete genome sequence and to reconstruct biochemical pathways of an organism. However, for the reconstruction of a specific class of biochemical pathways, namely metabolic pathways, information on chemical compounds and reactions is also required. The LIGAND database (1) has been organized to fill in the gap between genomic information and chemical information and applied to actual reconstruction of metabolic pathways in the completely sequenced organisms in KEGG (2,3).
The LIGAND database is a composite database comprising three sections: ENZYME for information on enzyme molecules and enzymatic reactions, COMPOUND for information on metabolites and other chemical compounds, and REACTION for the collection of substrate–product relations. We report here the current status of the LIGAND database and the new features of the COMPOUND section.
CURRENT STATUS OF LIGAND
LIGAND is constructed as a flat-file database and the data format of each section is similar to those of GenBank (4) and PIR (5) flat-files, a fixed number of columns are assigned to specify each field of entry (1).
The ENZYME section is based on the nomenclature of enzymes by IUBMB (International Union of Biochemistry and Molecular Biology) (6) and the Enzyme Handbook (7). Information regarding nomenclature by IUBMB is also available from the web at http://www.chem.qmw.ac.uk/iubmb/enzyme/ . The COMPOUND section contains a collection of chemical compounds that are found in the ENZYME section and in the KEGG/PATHWAY database, as well as other compounds found in the literature. The REACTION section is a collection of binary relations, namely substrate–product relations extracted from the ENZYME section and the KEGG/PATHWAY database.
The number of entries in the current release is summarized in Table 1.
Table 1. The number of entries in release 19.0 (October 1999) of the LIGAND database.
| Section | Content | Number |
|---|---|---|
| ENZYME | Entries | 3390 |
| Entries with reaction formula in chemical equations | 2906 | |
| Links to KEGG/PATHWAY (metabolic pathways) | 1734 | |
| Links to KEGG/GENES (gene catalogs) | 1099 | |
| Links to OMIM (human genetic disorders) (12) | 469 | |
| Links to PROSITE (proteins sequence motifs) (13) | 977 | |
| COMPOUND | Entries | 5645 |
| Entries with chemical formula | 3755 | |
| Entries with molecular structure | 4768 | |
| Links to ENZYME | 4536 | |
| Links to ENZYME as reactants | 4365 | |
| Links to ENZYME as cofactors | 82 | |
| Links to ENZYME as inhibitors | 154 | |
| Links to ENZYME as effectors | 33 | |
| Links to CAS | 1537 | |
| REACTION | Entries | 5200 |
| Reactions defined in ENZYME | 3084 | |
| Reactions with known enzymes in KEGG/PATHWAY | 3102 | |
| Reactions with unknown enzymes in KEGG/PATHWAY | 303 | |
| Non-enzymatic reactions in KEGG/PATHWAYa | 385 |
aNon-enzymatic reactions include reactions where it is not known whether enzymes are involved in catalysis.
NEW FEATURES OF COMPOUND
Compounds as interacting objects with proteins
Because chemical compounds in the COMPOUND section have roles in the living cell, they usually have interacting protein partners. At the moment, links are available only to the ENZYME section showing the relationship between chemical compounds and enzyme molecules. This kind of cross-reference information is quite useful to analyze the relationship between proteins and their ligands. Thus, we have added new link information to the PDB (8) and PROMISE (9) databases from the COMPOUND section.
We extract the information on heterogeneous group atoms from the PDB database and make a correspondence table between COMPOUND IDs and PDB HET codes. Then the links are automatically added to the DBLINKS field by the database update program. K. Degtyarenko (European Bioinformatics Institute), who develops the PROMISE database, kindly provided us with the link information between PROMISE and COMPOUND. We have also added it to the DBLINKS field.
Compounds in the ISIS database
For the purpose of substructure search of chemical compounds and for the ease of updating information of chemical compounds, we decided to maintain the COMPOUND section in the form of the ISIS/BASE database. Currently, all the information except for the DBLINKS (other than CAS) field is stored in the ISIS/BASE database. We generate the flat-file version of COMPOUND, which is made publicly available, by extracting the data from the ISIS database and by automatically merging computed link information.
We also plan to maintain the REACTION section in the ISIS/BASE database.
Classification of chemical compounds
Since a hierarchical classification of chemical compounds is useful for searching similar compounds and generic compounds, we started developing a classification scheme for the compounds in the COMPOUND section. A preliminary version of the classification is summarized in Table 2.
Table 2. Classification of chemical compounds and the number of entries in each class in release 19.0 (October 1999) of the LIGAND database.
| Class | Subclass | Number | |
|---|---|---|---|
| Carbohydrates | Monosaccharides | Aldoses | 21 |
| Ketoses | 12 | ||
| Deoxysugars | 7 | ||
| Aminosugars | 12 | ||
| Uronates | 11 | ||
| Disaccharides | 6 | ||
| Polysaccharides | 11 | ||
| Lipids | Fatty acids | 21 | |
| Fats | 6 | ||
| Phospholipids | 11 | ||
| Glycolipids | 6 | ||
| Steroid hormones | 7 | ||
| Other steroids | 5 | ||
| Eicosanoids | 26 | ||
| Nucleic acids | Bases | 5 | |
| Nucleosides | 9 | ||
| Nucleotides | 27 | ||
| Cyclic nucleotides | 10 | ||
| Peptides | Common amino acids | 20 | |
| Other amino acids | 35 | ||
| Amines | 11 | ||
| Peptide hormones | 5 | ||
| Neurotransmitters | 12 | ||
| Others | Fat-soluble vitamins | 7 | |
| Water-soluble vitamins | 11 |
AVAILABILITY
The LIGAND database is accessible through the WWW at http://www.genome.ad.jp/dbget/ligand.html . The user can then invoke the DBGET/LinkDB system (10,11) to retrieve the COMPOUND and ENZYME sections. Hierarchical classifications of enzymes and compounds can be viewed by the molecular catalog browser in the KEGG system at http://www.genome.ad.jp/kegg/kegg2.html . The periodic table for chemical elements is also available at the same URL.
The LIGAND database can be downloaded via anonymous FTP at ftp://kegg.genome.ad.jp/molecules/ligand/ . This directory contains all sections, COMPOUND, ENZYME and REACTION, including GIF image files and MDL-MOL files for compound structures. The same data set is mirrored at the NCBI repository ftp://ncbi.nlm.nih.gov/repository/LIGAND/
The basic concept of the LIGAND database has been published elsewhere (1). The present article reflects the most up-to-date version of the database and should be cited accordingly.
Acknowledgments
ACKNOWLEDGEMENTS
We thank Hiroko Ishida for extraction of reaction data from the KEGG pathway diagrams, Nobue Takeuchi for the input of new chemical structures, and Rumiko Yamamoto for converting the original COMPOUND section into ISIS format. This work was supported by a Grant-in-Aid for Scientific Research on the Priority Area ‘Genome Science’ from the Ministry of Education, Science, Sports and Culture of Japan. The computation time was provided by the Supercomputer Laboratory, Institute for Chemical Research, Kyoto University.
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