Control of the Metabolic Flux through the MEP Pathway
Plants produce an enormous variety of metabolites which can be categorised into those responsible for primary metabolism and those synthesizing secondary metabolites. Although secondary metabolites are not directly involved in the plant’s growth and development, they are essential for the plants survival through ecological interactions with the environment. A very large amount of secondary compounds are synthesized by the modification of common backbone structures. This structural variation of secondary metabolites is important for the ability of plants to adapt to environmental pressures such as pests and diseases. The isoprenoids (also called terpenoids) are the most diverse group of secondary metabolites with tens of thousands of compounds identified. Certain isoprenoid compounds are also involved in primary metabolism with functions in respiration, photosynthesis, and regulation of growth and development. Despite their diversities, all isoprenoids are biosynthesized from the same five-carbon (C5) isoprene building blocks, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). Different classes of isoprenoids are formed through the addition of different amounts of isoprene units to form hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), triterpenes (C30) and tetraterpenes (C40). With the exception of the hemiterpenes, the other classes of terpenoids are derived from prenyl diphosphate precursors which in turn are synthesized by prenyl synthases using one DMAPP and the corresponding amount of IPP units to form geranyl diphosphate (C10), farnesyl diphosphate (C15) and geranylgeranyl diphosphate (C20). It is to be expected that a metabolic pathway responsible for the biosynthesis of such a wide variety of compounds should be finely regulated to meet the demands of different tissues, organs and growth stages.
Until recently, all IPP and DMAPP were thought to be formed only through the mevalonate pathway. The mevalonate pathway synthesizes IPP from acetyl-CoA via mevalonic acid and produces DMAPP with an isomerisation step. Recently, however, an alternative pathway was discovered, which uses pyruvate and glyceraldehyde 3-phosphate as substrates. This pathway is known as the non-mevalonate, deoxyxylulose 5-phosphate (DXP) or methylerythritol 4-phosphate (MEP) pathway (Fig. 1). Although most organisms use only one of these pathways for synthesizing terpenoids, plants use both. These two pathways are compartmentalized in plants with the mevalonate pathway producing IPP and DMAPP in the cytosol, and the non-mevalonate pathway IPP and DMAPP in the plastids. Generally the mevalonate pathway provides substrate for the synthesis of sterols, sesquiterpenes and ubiquinones, whereas the plastidial pathway provides substrate for synthesizing hemi-, mono-, and di-terpenes, as well as carotenoids and the phytol chain of chlorophyll. The occurrence of a second pathway for producing the isoprene building blocks introduced a new level of complexity in understanding the control and regulation of isoprenoid biosynthesis. This new pathway seems to be much more important in producing products involved in ecological interactions than the mevalonate pathway, and thus may be regulated in more diverse ways.
Many isoprenoid compounds produced through the MEP pathway have important commercial value, eg. taxol for cancer treatment, artemisinin as an anti-malarial drug and β-carotene and α-tocopherol as nutrients important for human health. Attempts to manipulate iosprenoid production frequently lead to undesirable results. Problems encountered include the lack of sufficient substrate and further metabolism of transgenetically introduced metabolites into other compounds. Alteration of isoprenoid metabolism can also lead to unexpected and undesired phenotypes such as dwarfism. Knowledge of the mechanisms of regulation of the MEP pathway may overcome these problems and lead to increased production of physiologically active and / or commercially valuable isoprenoids. Understanding secondary metabolism in terms of control and regulation may also shed light on the biological activity and function of secondary metabolites.