Biosynthetic Pathways for Secondary Metabolites

The importance of secondary metabolites of plants is still very much underestimated. Organic chemists have often expressed an interest in these "natural compounds," but mainly as a means to sharpen their capacity for structure determination, the reward being the elucidation of an as yet not described structural skeleton. Because an important fraction of our pharmaceuticals are still derived from plant origins, it was also often rewarding to chemically synthesize these compounds, particularly when the active component was isolated from a rare or difficult to cultivate species. Frequently, therefore, an enormous amount of effort has gone into the identification and synthesis of minute amounts of a new compound that only ended up being an addition to the ever growing encyclopedia of known organic compounds.

As discussed above, the fascinating progress in plant molecular biology has created a huge potential for the characterization of biosynthetic pathways and the physiological activities of compounds. This imparts an entirely new importance and significance to plant secondary metabolite studies. These molecules are synthesized through interactions with enzymes and have evolved in nature through their capacity to bind target macro-molecules, mostly proteins. They are thus ideal starting products for the development of drugs or agrochemicals that interact tightly with a given target protein, be it a receptor, an enzyme, a signaling or a regulatory protein.

Until now, although more than 8,000 proteins have been crystallized and their three-dimensional structure determined, it turns out that only 650 different protein folds have been identified.6 This means that all proteins, whether from microbial, plant, invertebrate or vertebrate origin, are built up using a limited number of three-dimensional structures. Hence, by applying a high throughput screening for compounds interacting with a given receptor protein, specific molecules can be isolated that interact with a characteristic protein fold. Such a compound will be an ideal starting molecule for further drug design. Plant molecular biologists now have the tools to isolate the genes involved in its biosynthesis and engineer the pathway in a fast growing plant. In this way, an abundant or continuous production can be assured. The compound can then be the starting material for combinatorial chemists who will synthesize variants that better fit the fold in the target protein against which a drug needs to be developed.

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