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Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Brian Yu, Nikola Sladojevic, James K. Liao
Inhibition of the conversion of HMG-CoA to L-mevalonate by statins prevents the synthesis of downstream isoprenoid intermediates of the cholesterol pathway, including fernesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) (Goldstein and Brown, 1990). Both FPP and GGPP serve as vital lipid attachments for a variety of proteins, including ubiquinone, heme A, the γ subunit of heterotrimeric G-proteins, the small GTPase Ras, and Ras-like proteins including Rho, Rab, Rac, Ral, and Rap (Liao and Laufs, 2005). Prenylation, or addition of hydrophobic molecules to a protein, facilitates cell membrane association, and is required for activation and function of the small GTPases. In particular, members of the Ras and Rho GTPase subfamilies are major substrates for prenylation, and indeed are central to mediating the pleiotropic effects of statins. As small GTP-binding proteins, members of the Ras and Rho families cycle between the inactive GDP-bound state and active GTP-bound state at the plasma membrane (Fig. 10.4). Without prenylation, Ras and Rho GTPases accumulate in the cytoplasm (Michaelson, 2001).
Terpenoids: The Biological Key Molecules
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Moumita Majumdar, Dijendra Nath Roy
Prenylation of proteins is one of the principle signalling pathways. The prenylated proteins are attached to the cell membrane and transport a signal to the next receptor through conformational changes. Protein prenylation was first identified in fungi in 1978 (Kamiya et al. 1978), and the first prenylated protein, farnesylated lamin B, was discovered in mammalian cells (Wolda and Glomset 1988; Farnsworth et al. 1989). Protein prenylation is accompanied mainly by farnesylation and by geranylgeranylation, which is an irreversible covalent post-translational modification found in all eukaryotic cells. Three prenyltransferase enzymes catalyse the associated reactions. Attachment of a single farnesyl (C15) or geranylgeranyl (C20) isoprenoid group is catalyzed by farnesyltransferase (FTase) and geranylgeranyltransferase type 1 (GGTase-I), respectively, to a cysteine residue located in a C-terminal consensus sequence commonly known as the CaaX box (Figure 3.1), where ‘C’ is cysteine, ‘a’ generally signifies an aliphatic amino acid and the ‘X’ residue defines which isoprenoid group is attached to the target protein (Bueno et al. 2015). Geranylgeranyltransferase type 2 (GGTase-II or Rab geranylgeranyltransferase) catalyses the addition of two geranylgeranyl groups at two cysteine residues in sequences such as CXC or CCXX close to the C terminus of Rab proteins.
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
Protein prenylation, in particular farnesylation and geranylgeranylation, is one of the essential post-translational protein modifications in the eukaryote in which protein prenyltransferases catalyze the transfer of FPP or GGPP to cysteine residues located in conserved prenylation target motifs at the C-terminus of the protein substrate (Clarke, 1992; Merino et al., 2017). This post-translational modification is required for the proper membrane localization and biological function of numerous proteins (Hancock et al., 1989; Kitten and Nigg, 1991; Zhang and Casey, 1996).
Effects of cadmium stress on the morphology, physiology, cellular ultrastructure, and BvHIPP24 gene expression of sugar beet (Beta vulgaris L.)
Published in International Journal of Phytoremediation, 2023
Dali Liu, Zhuo Gao, Jiajia Li, Qi Yao, Wenbo Tan, Wang Xing, Zhenqiang Lu
In addition, when plants are subjected to heavy metal stress and metal toxicity, ions can be chelated with ion-trafficking proteins or small-molecule ligands that either guide and insert ion cofactors into the target enzyme or catalyze electron transport and redox transformations after entering cells. The chelate complexes can be transported to intracellular compartments by metallochaperones for metal sequestration and homeostasis in cells (Huffman and O'Halloran 2001; Dupont et al.2010). Metallochaperones are generally soluble intracellular proteins that tightly bind to metal ions to prevent them from causing damage to other cellular components (de Abreu-Neto et al.2013). Most metallochaperones contain a highly conserved MXCXXC motif with a ferredoxin-like structural fold (βαββαβ), which can bind the heavy metals Cd2+, Cu2+, or Zn2+ (Tehseen et al. 2010). Heavy metal-associated isoprenylated plant proteins (HIPPs) are important metallochaperones that contain both heavy metal-associated domains and prenylation motifs, and these characteristics enable HIPPs to be used for metal detoxification (Barth et al.2009; de Abreu-Neto et al.2013). The putative metal-binding protein CdI19 contains two heavy metal-binding motifs and a conserved prenylation site, which plays an important role in the maintenance of heavy metal homeostasis. Cd2+ can induce the expression of AtCdI19, and overexpression of CdI19 in Arabidopsis can enhance tolerance to Cd (Suzuki et al.2002).
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
In vertebrates, this class of pharmaceuticals is well known to inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) which is the rate-limiting enzyme in the MVA pathway responsible for biosynthesis of cholesterol (Al-Habsi, Massarsky, and Moon 2016; Blumenthal 2000; Endo, Kuroda, and Tsujita 1976; Fent, Weston, and Caminada 2006; Sehayek et al. 1994). In addition to cholesterol, the MVA pathway is also involved in the synthesis of other important non-sterol isoprenoids, such as coenzyme Q and geranylgeranyl pyrophosphate (GGPP), which play an essential role in cellular physiology (Figure 1) (Beltowski, Wójcicka, and Jamroz-Wiśniewska 2009). The effects of statins on the kinetics of enzymes involved in the MVA pathway were examined extensively in mammals but, to the best of our knowledge, few mechanistic studies were undertaken in aquatic organisms. In humans and mammalian models, statins have been associated with pleiotropic effects, such as prevention of cardiovascular diseases, anticancer activity, immunomodulation, and neuroprotection (Chen et al. 2016; Freed-Pastor et al. 2012; Schointuch et al. 2014). It is noteworthy that statins are also known to exert several adverse effects including myopathy, cognitive dysfunction, and diabetes, which are associated with either depletion of coenzyme Q, protein prenylation, and dolichol (final end products of the MVA pathway in the non-sterol branch) or with cellular acetyl-CoA accumulation involving mechanisms linked with alterations in the energy metabolism (Figure 1) (Beltowski, Wójcicka, and Jamroz-Wiśniewska 2009; Du Souich, Roederer, and Dufour 2017; Greenwood, Steinman, and Zamvil 2006; Sirvent et al. 2012).