Cytosolic mevalonate pathway, products

Terpenoids are derived from the cytosolic mevalonate pathway or from the plastidial 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway (see also Terpenoid Biosynthesis). Both pathways lead to the formation of the C5 units isopentenyl diphosphate and its allylic isomer dimethylallyl diphosphate, which are the basic terpenoid biosynthesis building blocks (Fig. 1). Although increasing evidence suggests that exchange of intermediates occurs between these compartments, the cytoplasmic mevalonate pathway is generally considered to supply the precursors for the production of sesquiterpenes and triterpenes (including sterols) and to provide precursors for protein prenylation and for ubiquinone and heme-A production in mitochondria. In the plastids, the MEP pathway supplies the precursors for the production of isoprene, monoterpenes, diterpenes (e.g., GAs), and tetraterpenes (e.g., carotenoids). 

Fig. 2. A section of the isoprenoid pathway illustrating the branch to rubber biosynthesis. Rubber (the product) is synthesized in the cytosol from one molecule of allylic pyrophosphate (the initiator) and many molecules of isopentenyl pyrophosphate (the monomer). Isopentenyl pyrophosphate is produced by the cytosolic mevalonate pathway and by the plastidic methyl-erythritol pathway, as indicated by the shaded boxes. GPP, geranyl pyrophosphate FPP, farnesyl pyrophosphate GGPP, geranylgeranyl pyrophosphate.

Acetyl-CoA has already been mentioned as a key precursor for many industrially relevant compounds. For example, it is a direct precursor for the mevalonate pathway to obtain isoprenoids. It is also a key precursor for malonyl-CoA, yielding the production of fatty acids (biodiesel) and polyketides [19]. The challenge of engineering the acetyl-CoA availability in yeast lies in its compartmentalization. While acetyl-CoA is readily available in the mitochondrium, the cytosolic pool is low. The cytosolic pool of acetyl-CoA is fed from acetate, which is activated by a bond to coenzyme A at the expense of 1 ATP. It becomes therefore obvious that any metabolic pathway using cytosolic acetyl-CoA aiming at mass production is energetically detrimental and inefficient - if not recombinantly redesigned [20]. 

AcCoA is the building block of fatty acids, polyketides, and mevalonic acid (MVA), a cytosolic precursor of the C5 isoprene units for the biosynthesis of terpenes in the C,5 and Cj series (mind it is different from the MEP pathway, in product, and in cell location). Finally, AcCoA enters the citric acid or Krebs cycle, which leads to several precursors of amino acids. These are oxaloacetic acid, precursor of aspartic acid through transamination (thus toward lysine as a nitrogenated C N linear unit and methionine as a methyl supplier), and 2-oxoglutaric acid, precursor of glutamic acid (and subsequent derivatives such as ornithine as a nitrogenated C N linear unit). All these amino acids are key precursors in the biosynthesis of many alkaloids. 

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