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Terpenoids in Treatment of Immunological Disease
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Avik Sarkar, Surajit Bhattacharjee
Terpenoids are made from five-carbon isoprene units (C5H8) and because of this they are also called isoprenoids; they represent a diversified group of small molecules synthesized by plants. The diverse and complex terpenoid molecules are synthesized from the simple isoprenoid molecule with the help of a large family of terpenoid synthases (Bouvier et al., 2005; Keeling and Bohlmann 2006; Tholl 2006). The synthesis of the basic terpenoid ring takes place by the formation of linear prenyl pyrophosphates—geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP) and geranyl geranyl pyrophosphates (GGPP)—through the action of three different prenyltransferase enzymes (Figure 6.1). These prenyl pyrophosphates serve as precursors for the synthesis of various terpenoids like monoterpenoids, sesquiterpenoids and diterpenoids. Terpenoid synthases catalyse the formation of the aforementioned terpenoids. On the other hand, synthesis of triterpenoids also occurs by conversion of oxidosqualene to cyclic triterpenoids by oxidosqualene cyclases (Figure 6.1).
Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
In 2006, the yeast was genetically modified in order to produce more farnesyl pyrophosphate through the mevalonate pathway and to reduce its use for sterol biosynthesis (down regulation of squalene synthase). Moreover, the gene coding for amorphadiene synthase and CYP71AV1 from A. annua were introduced and a final concentration of 100 mg l–1 of artemisinic acid were produced (Ro et al., 2006).
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
Apart from the growing body of evidence suggesting that the imbalance of cholesterol homeostasis plays an important role in several diseases of the CNS (Backes and Howard 2003; Baytan et al. 2008; Kirsch, Eckert, and Mueller 2003; Marz, Otten, and Miserez 2007; Schulz et al. 2004; Vance 2012), the reduction of MVA pathway end-products in non-sterol branch, such as coenzyme Q (CoQ), farnesyl pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) were suggested to be related with an impairment in brain energy metabolism as these end-products are associated with mitochondrial electron transport chain (Figure 1) (Mans, McMahon, and Li 2012; Oks et al. 2018). In the mitochondria, CoQ is responsible for electron transport during oxidative phosphorylation, ensuring ATP production in all cell types including neurons (Figure 1) (Littarru and Langsjoen 2007). In addition, a large number of molecules use FPP and GGPP as lipid moieties and its depletion, due to MVA inhibition by statins, affects a large variety of essential intracellular signaling pathways and functions, including respiratory chain activity, particularly the complex IV (Figure 1) (Arenas et al., 2003; Mans, McMahon, and Li 2012; Ramachandran and Wierzbicki 2017). In the present study, exposure to the intermediate concentrations of SIM (40 ng/L and/or 200 ng/L) induced significant alterations in transcript levels of zebrafish brain cox4i1 and cox5aa (Figure 2). These genes play an important function in the complex IV (COX enzymatic complex) of the electron transport chain (Figure 1), which is responsible for the maintenance of a proton gradient in the mitochondrial membrane and for continuous electron flow via oxidative phosphorylation (Rousseau and Han 2002). Previous investigations in humans reported a decrease of COX activity in skeletal muscle of patients treated with statins, which was associated with a depletion of FPP in the MVA pathway (Arenas et al., 2003; Duncan et al. 2009; Mans, McMahon, and Li 2012). These studies disclosed that statins treatment leads to an impairment of the electron transport chain, limiting aerobic cellular respiration. Consequently, cellular metabolism may shift from aerobic to anaerobic, which produces lower amounts of ATP (De Vivo and DiMauro 1990). Although the impairment of the electron transport chain affects mainly the muscle function, the brain is also highly susceptible to mitochondrial disruption (De Vivo and DiMauro 1990). Similar to the studies in humans mentioned above, our results reported a downregulation of cox4i1 and cox5aa suggesting that SIM is able to disrupt the electron transport chain in zebrafish brain. Since the brain is highly energy dependent, these alterations might initiate marked adverse effects in fish populations, since the brain is the regulatory center of whole body and small changes in energy metabolism are expected to affect a large number of biological processes.