The MVA pathway was the first isoprenoid biosynthesis pathway discovered. It is active in plant cytosol, fungi, archaebacteria, eubacteria, and some protozoa groups [2,6]. This pathway starts with the condensation of an acetyl-coenzyme A (acetyl-CoA) molecule with acetoacetyl-CoA to yield 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA), a reaction catalyzed by HMG-CoA synthase. Then, the enzyme HMG-CoA reductase (HMGR), produces MVA. This enzymatic step can be inhibited by statins (e.g., simvastatin, lovastatin, atorvastatin, or pitavastatin) [7]. Finally, MVA is phosphorylated twice and decarboxylated to yield IPP/DMAPP. Alternatively, the MEP pathway is present in plant plastids, bacteria, and some protozoa groups, including apicomplexan parasites [2,6]. The MEP pathway starts with the condensation of glyceraldehyde 3-phosphate with pyruvate to form 1-deoxy-D-xylulose-5-phosphate (DOXP). This step is catalyzed by the 1-deoxy-D-xylulose 5-phosphate synthase (DXS). DOXP is next transformed to MEP by the enzyme 1-deoxy-D-xylulose 5-phosphate reductase (DXR). Importantly, DXR can be inhibited by fosmidomycin, which could thus be considered to be the homolog of statins on the MEP pathway. Remarkably, fosmidomycin has been proposed as an antibiotic for several protozoa and bacterial diseases [8,9]. Next in the pathway, MEP suffers modifications, including its condensation with CTP, a subsequent condensation with an ATP molecule, and a reduction. After these steps, hydroxymethyl-butenyl pyrophosphate (HMBPP) is produced. Later, this metabolite is converted into IPP/DMAPP by the enzyme hydroxymethyl-butenyl diphosphate reductase (LytB).

Regardless of the biosynthetic pathway, IPP and DMAPP can be interconverted by the IPP isomerases. In plants, IPP can be directly used for the production of phytohormones [10]. However, most isoprenoid-dependent pathways require isoprenic chains with lengths greater than one isoprenic unit. The first elongation step is the condensation of IPP and DMAPP to form geranyl pyrophosphate (GPP; 10 carbon), this step is catalyzed by the enzyme GPP synthase (GPPs). GPP can be condensed again with an IPP molecule to form farnesyl pyrophosphate (FPP; 15 carbon), with the help of the FPP synthase (FPPs), the enzyme target of bisphosphonates (e.g., alendronate, risedronate), which is widely used as a drug in the treatment of osteopenia and osteoporosis. Similarly, the geranylgeranyl pyrophosphate synthase (GGPPs) catalyzes the production of geranylgeranyl pyrophosphate (GGPP; 20 carbon) by condensing FPP with one more IPP molecule. After the formation of GGPP, several enzymes continue to extend the isoprenic chain to form longer structures: for example, octaprenyl pyrophosphate (8 isoprenic units); nonaprenyl pyrophosphate (9 isoprenic units; also known as solanesyl pyrophosphate); polyprenols of 13–21 isoprenic units; or even longer ones, such as natural rubber (>300 isoprenic units) [11,12]. Isoprenic moieties can suffer various chemical modifications. For example, in most photosynthetic organisms, hydrogenation of GGPP to phytyl pyrophosphate (phytyl-PP) is known to occur. Later, this phytyl-PP serves as a precursor for chlorophyll, tocopherols (vitamin E), and phylloquinone biosynthesis (vitamin K1) [13]. Another example is the reduction polyprenols, of 13–21 isoprenic units, to dolichols in eukaryotic organisms. Dolichols are phosphorylated to dolichyl-P by a dolichol kinase and then mainly employed as lipid anchors for sugar transport in the eukaryotic protein glycosylation and GPI biosynthesis pathways [14,15].

In any case, all polyprenyl pyrophosphates cited previously are employed as substrates for diverse anabolic pathways. For example, FPP and GGPP can be employed for an important post-translational modification of proteins. Typically, protein prenylation occurs when farnesyl or geranylgeranyl moieties are attached to soluble proteins, resulting in their anchoring to membranes. The most studied prenylated proteins are Ras, Rho, and Rap, which are small GTPases involved in cellular signaling and intracellular trafficking [16,17]. This post-translational modification is catalyzed by specific transferases that attach the FPP or GGPP moieties to the C-terminal cysteine residues of proteins containing the conserved motif for prenylation CAAX (C = cysteine, A = aliphatic amino acid, X = diverse terminal residue) [16,17]. Interestingly, alternative isoprenoid moieties were identified when linked to proteins. For example, in plants, a phytylation of proteins also occurs, in this case using phytyl-PP instead of FPP or GGPP [18], and protein dolichylation occurs in malaria parasites and human colon carcinoma cells [19,20]. Besides protein prenylation, polyprenyl pyrophosphates also play a role as constituents of membranes in plants [21,22,23], are required for the formation of menaquinone in bacteria (vitamin K2; requires GGPP) [24], and in the biosynthesis of sterols, like cholesterol in animals (requires FPP) [25]. Finally, polyprenyl-PPs also plays an important part in respiratory processes and lipoperoxidation defense. These molecules are necessary for the biosynthesis of ubiquinones (coenzyme Q), a metabolite that forms part of the electron transport chain at the mitochondrial membrane and an antioxidant cofactor elsewhere. The biosynthesis of ubiquinones involves the condensing of a benzoquinone ring with a polyprenyl-PP moiety of 6–10 isoprenic units; the actual length of the isoprene depends on the organism [26,27].

Isoprenoid biosynthesis is the target of some of the most prescribed drugs worldwide, as already cited. For example, statins are employed to treat hypercholesterolemia, as they inhibit mammalian biosynthesis of cholesterol, while bisphosphonates are used in the treatment of osteoporosis due to their ability to accumulate in bone mineral, inhibiting osteoclast activity [7,28,29]. Finally, fosmidomycin has been purposed as an antibiotic for the treatment of MEP-pathway-dependent protozoa and bacteria [8,30].

2. The Origin of Geranylgeraniol and Farnesol