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Nature relies on an intricate network of biosynthetic pathways to produce the cornucopia of small organic molecules needed to support life. Among these, the isoprenoids are extraordinarily diverse in chemistry and structure. Over 23,000 individual isoprenoid compounds have been characterized, and hundreds of new structures are reported each year. They serve as visual pigments, reproductive hormones, defensive agents, constituents of membranes, components of signal transduction networks, mating pheromones, and photoprotective agents, to name only a few of their many roles. Abnormalities associated with the pathway can cause coronary heart disease and cancer, while at the same time some isoprenoid compounds, such as taxol, offer promise as potent new drugs.
Most of the molecular diversity in the isoprenoid pathway is created from the diphosphate esters of simple linear polyunsaturated allylic alcohols such as dimethylallyl alcohol (a 5-carbon molecule), geraniol (a 10-carbon molecule), famesol (a 15-carbon molecule), and geranylgeraniol (a 20-carbon molecule). The hydrocarbon chains are constructed one isoprene unit at a time by addition of the allylic moiety to the double bond in isopentenyl diphosphate, the fundamental five-carbon building block in the pathway, to form the next higher member of the series (see the figure). Geranyl, famesyl, and geranylgeranyl diphosphates lie at multiple branch points in the isoprenoid pathway and are substrates for many enzymes. These are primarily cyclases, which are responsible for generating the diverse carbon skeletons for the synthesis of the thousands of mono-, sesqui-, di-, and triterpenes; sterols; and carotenoids found in nature. The structures of three of these cyclases are reported on pages 1811, 1815, and 1820 (1-3) of this issue yielding clues to how this is accomplished.
The chain elongation and cyclization reactions of isoprenoid metabolism are electrophilic alkylations...