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Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
The chemical structure of isoprenoids consisting of multiple units of five carbon atoms and their biosynthesis derived from the consecutive condensation of single precursors: the monomer IPP (isopentenyl diphosphate) and its isomer DMAPP (dimethylallyl diphosphate) (Boronat and Rodriguez-Concepcion, 2015). IPP is synthesized in the cytosol and endoplasmic reticulum from key regulatory enzyme acetyl-CoA through mevalonate pathway, in which mevalonate is transformed in IPP by two consecutive reactions of phosphorylation and subsequent decarboxylation (Eberl et al., 2003). In mammals the enzyme IPP isomerase is responsible for the isomerization of IPP to DMAPP, while farnesyl pyrophosphate synthase (FPPS) catalyzes two consecutive condensations between IPP and DMAPP providing geranyl diphosphate (GPP), precursor of monoterpenes and farnesyl diphosphate (FPP) precursor of sesquiterpenes, triterpenes and sterols (via squalene biosynthesis) as well as other important secondary metabolites like ubiquinones and dolichols. An ulterior condensation between one molecule of IPP and one molecule of FPP, catalyzed by the geranylgeranyl pyrophosphate synthase (GGPPS), forms geranylgeranyl pyrophosphate (GGPP), precursor of di- and tetraterpenes and carotenoids (Fig. 2.1) (Zhao et al., 2013). In higher plants and other microorganisms the first step of synthesis of IPP occurs in the plastids through the condensation of pyruvate with glyceraldehyde-3-phosphate to form the intermediate 1-deoxyxylulose5-phosphate (DXP)-also called methylerythritol (MEP)-(MEP pathway). Biosynthesis of isoprenoids.
Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Susana Barros, Ana M. Coimbra, Nélson Alves, Marlene Pinheiro, José Benito Quintana, Miguel M. Santos, Teresa Neuparth
Zebrafish was selected to conduct this experiment since it is one of the recommended test species for ecotoxicological studies (Segner 2009) and due to its close phylogeny with mammalians, with highly conserved genes and protein functions (Fang and Miller 2012). The brain was selected for the present study, since it is the main organ responsible for regulating energy homeostasis in the body. Due to its high lipophilicity, SIM is able to cross the blood-brain barrier (BBB) (Moghadasian 1999), making the brain an interesting case study, since the influence of SIM on the central nervous system (CNS) is still poorly understood. The main substrate for energy production in the brain is glucose that is transported through the BBB by the glucose transporters (glut1b), which gene expression may be affected by cholesterol levels (Patching 2017; Xiuli, Meiyu, and Guanhua 2005) (Figure 1). Once inside the cell, glucose participates in glycolysis and produces tryptophan, a process in which the gene encoding glyceraldehyde 3-phosphate dehydrogenase (gapdh) plays a major role (Ganapathy-Kanniappan 2018; Seidler 2013). After being transported to the mitochondrial matrix, tryptophan produces acetyl-CoA, which in cases of low amounts of glucose, may be obtained by fatty acid β-oxidation carried out by the medium-chain acyl-CoA dehydrogenase (acadm) (Eaton, Bartlett, and Pourfarzam 1996; Hashimoto 1999). As fatty acids are too large to cross the BBB, these molecules are synthesized in the cytosol of brain cells from available acetyl-CoA through the action of acetyl-CoA carboxylase alpha (accα) and fatty acid synthase (fasn) (Lyssimachou et al. 2015) (Figure 1). Mitochondrial acetyl-CoA then feeds the tricarboxylic acid cycle, in which the isocitrate dehydrogenase encoding gene (idh3a) is essential (Findlay et al. 2018; Sazanov and Jackson 1994), and the resulting products are sent to the electron transport chain. The electron transport chain is the predominant ATP producer, and several MVA pathway end products influence this process, such as ubiquinones – CoQ (essential for the maintenance of the electron transport between complexes) (Figure 1), as well as geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP) that were found to affect complex IV of the electron transport chain, where genes cytochrome c oxidase subunits 4i1 (cox4i1) and 5aa (cox5aa) play major roles (Arnold 2012; Fornuskova et al. 2010; Kadenbach et al. 2000) (Figure 1). Following the key role of the above-mentioned genes, the aim of this study was to examine the effects of SIM on the expression pattern of genes involved in the regulation of brain energy metabolism.