**2.1 Physiology of cholesterol synthesis**

Cholesterol, synthesized in the mevalonate pathway from HMGCoAR (**Figure 2**) [3], is regulated in response to different stimuli [3]. This pathway also generates [1, 2] farnesyl pyrophosphate (FPP), precursor of sterols, such as cholesterol; ubiquinone, necessary for the mitochondrial electron transport chain; dolichols, for the protein N-glycosylation; carotenoids, free radical scavengers; isoprenoids, to anchor proteins to cell membranes [2]; and geranylgeranyl pyrophosphate (GGPP), involved in a wide

### **Figure 1.**

*The mevalonate (MVA) pathway and its connection to intracellular energy metabolism signaling. The fatty acid synthesis and β-oxidation pathway; glycolysis and the TCA cycle are noteworthy among other.*

### **Figure 2.**

*Diagram of the MVA pathway. Acetyl-CoA is converted to hydroxymethylglutaryl-CoA (HMG-CoA) used by HMGC reductase (HMGCR) to synthesize MVA. MVA generates farnesyl pyrophosphate (FPP), precursor of some sterols, such as membrane cholesterol; as well as ubiquinone (Coenzyme Q ) from the mitochondrial electron transport chain; dolichols, for protein N-glycosylation; carotenoids, free radicals' scavenger; and isoprenoids, for membranal protein anchoring. FPP is converted into geranylgeranyl pyrophosphate (GGPP), both essential in prenylation processes.*

### **Figure 3.**

*Antitumoral effects of MVA pathway inhibition. MVA pathway inhibition inhibits tumor growth and progression through reduction in MVA synthesis, which decreases isoprenoid levels, preventing protein prenylation, translocation of Rho and Ras to the cell membrane, and inhibition of cholesterol synthesis.*

### **Figure 4.**

*Signal transduction through Rho-GTP proteins. Rho proteins are present in an active state, bound to GTP, and an inactive state, bound to GDP. When GTP binds to Rho proteins, a change in protein structure is produced that allows information to be processed and the signal to be propagated within the cell. The Rho proteins change cyclically between their active and inactive forms, these reactions being catalyzed by the "guanine-nucleotideexchange factors" proteins (GEFs); by the "GTPase-activating proteins" (GAPs), and by the "guanine-nucleotide" "proteins-dissociation inhibitors" (GDIs). Among the effectors downstream of Rho (***Figure 4***), the Rhodependent kinase (ROCK) family of MAP kinase proteins stands out.*

range of cellular processes (**Figure 3**) [3]. Prenyltransferases farnesyl transferase (FTase) and geranylgeranilatransferase (GGTase I and II) activate the functions of some FPP or GGPP-dependent proteins in the cell membrane [3, 5, 12]. Thus, Ras protein regulates cell differentiation and proliferation; Rho controls the cytoskeleton and cell growth progression (**Figure 4**) [3, 13]; Rab, acts in the transport of intracellular vesicles; Rap, is essential in cell replication, platelet activation and generation of oxygen radicals; and G proteins, necessary in the signal transduction process [6]. Therefore, blocking the mevalonate pathway would lead to dysfunctional proteins due to disruption of the prenylation process (**Figure 3**) [3, 7].
