Chemical Knowledge for Predicting Biosynthetic Pathways of Secondary Metabolites

Metabolism is a chemical aspect of life that produces metabolites and energy by chemical reactions catalyzed by enzymes. Metabolic reactions that synthesize basic metabolites such as nucleic acids, carbohydrates, and amino acids are shared by various organisms. Those that synthesize secondary metabolites such as antibiotics, toxins, dyes and hormones are specific to individual organisms. Most of the known secondary metabolites have biological activities that are valuable for medical and agricultural uses. While basic metabolic pathways are well studied and collected in the LIGAND, PATHWAY, REACTION databases in Kyoto Encyclopedia of Genes and Genomes [2, 3], pathways for the biosynthesis of secondary metabolites are only partly or scarcely studied. Genome sequence analysis provides a source of the information necessary for predicting the biosynthesis pathways for secondary metabolites because the sequence analysis could reveal all the enzymes specific to each organism from their genes coded on the genome. Metabolic pathway is reconstructed by predicting intermediate reactions stepwise in the direction reverse to biosynthesis; from a given secondary metabolite to a starting basic metabolite. At each prediction step, more than one reactions are usually proposed as the candidates for the next intermediate reaction because each intermediate metabolite usually have several possible reaction sites in its chemical structure. To select the most probable reaction, knowledge is required to evaluate the chemical reactivity of the candidates. We have analyzed metabolic reactions to obtain chemical knowledge on the reactions in the cells. We are accumulating two different types of chemical knowledge for the prediction of metabolic pathways. The one is related to the substrate and reaction specificity of the enzymes. The other type of chemical knowledge is related to the preference in the chemical reactions in the cells. These two are supplemental to each other.