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Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Sayantan Maitra, Dibyendu Dutta
The precursor of the quinone ring is only 4-hydroxybenzoic acid (4-HB), which is derived from tyrosine. Mevalonate pathway is the main route to synthesize the isoprenoid tail, which is also common to cholesterol biosynthesis. The initial part of the mevalonate pathway involves the condensation of three acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA by HMG-CoA reductase, which is the main regulatory enzyme in cholesterol biosynthesis. Mevalonate is subsequently phosphorylated in two steps by mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK). Then, decarboxylation of mevalonate pyrophosphate yields isopentenyl pyrophosphate (IPP), which is the precursor of farnesyl pyrophosphate (FPP) and the building block for the biosynthesis of dolichol and the side chain of CoQ. Isomerization of IPP gives dimethylallyl pyrophosphate (DMAPP), and FPP synthase utilizes IPP and DMAPP to make FPP with the intermediary formation of geranyl pyrophosphate (GPP). FPP is further converted into cholesterol, dolichols, and CoQ [6]. Decalyprenyl diphosphate synthase (DPS) is a heterotetramer consisting of two different proteins, namely, PDSS1 and PDSS2. DPS catalyzes the condensation of IPP and FPP to produce ten units of prenyldiphosphate (decaprenyl diphosphate). 4-Hydroxybenzoic acid-decaprenyl diphosphate transferase (encoded by CoQ2 gene in humans) catalyzes the condensation of PHB with the isoprenoid tail to yield CoQ10 [7,8].
Biogeneration of Volatile Organic Compounds in Microalgae-Based Systems
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
Pricila Nass Pinheiro, Karem Rodrigues Vieira, Andriéli Borges Santos, Eduardo Jacob-Lopes, Leila Queiroz Zepka
Geosmin and 2-methylisoborneol (2-MIB) are synthesized through the isoprenoid pathways, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMADP), and are the central intermediates in the isoprenoid biosynthesis. They can be produced in the mevalonate pathway (MVA) or methylerythritol phosphate (MEP) pathway. Subsequently these starter molecules are converted to immediate prenyl diphosphate precursors, such as geranyl diphosphate (GDP) and farnesyl diphosphate (FDP) (Liato and Aïder 2017; Meena et al. 2017). The cyclization of farnesyl diphosphate (FDP) to geosmin is catalyzed by geosmin synthase via three steps (farnesyl diphosphate to germacradienol, germacradienol to 8,10-dimethyl-1-octalin, and 8,10-dimethyl-1-octalin to geosmin) in cyanobacteria (Giglio et al. 2008). The 2-MIB synthase mechanism is based 2-C-methyltransferase catalyzed methylation of geranyl diphosphate, C10 monoterpene precursor, into 2-methylgeranyl diphosphate. Then, 2-MIB synthase catalyzes cyclization of the 2-methylgeranyl diphosphate to 2-MIB (Lee et al. 2017).
Natural Polyketides to Prevent Cardiovascular Disease
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Additionally, there are pleiotropic effects that the inhibition of the mevalonate pathway may incur as a result of this pathway’s role in the production of a number of key isoprenoid intermediaries. The effect is due to the role that prenylation, the addition of hydrophobic molecules to a protein, plays in protein trafficking and cellular signaling by facilitating protein-membrane interactions. First, farnesyl pyrophosphate signals protein transport to the lumen of the endoplasmic reticulum for further modification and is implicated in interactions involving Ras family proteins. Second, geranylgeranyl pyrophosphate plays a role in the modulation of the RhoA, Rac and Cdc signaling pathways. These are integral GTPase proteins for cellular growth, proliferation and migration that are employed ubiquitously across normal cell types and are often the subject of mutation in tumorigenic cells (Liao and Laufs, 2005).
Simvastatin Attenuates Glucocorticoid-Induced Human Trabecular Meshwork Cell Dysfunction via YAP/TAZ Inactivation
Published in Current Eye Research, 2023
Hannah Yoo, Ayushi Singh, Haiyan Li, Ana N. Strat, Tyler Bagué, Preethi S. Ganapathy, Samuel Herberg
Simvastatin, a member of the cholesterol-lowering statin drug class, inhibits HMG-CoA reductase that catalyzes the production of mevalonate. The anabolic mevalonate cascade provides key isoprenoid metabolites for diverse cellular processes including cholesterol synthesis and post-translational membrane targeting of Rho GTPases.79,80 Furthermore, it was recently demonstrated that the mevalonate pathway has a profound impact on the function of the transcriptional regulators YAP and TAZ in different cancer cells.40,63,81 These studies mechanistically linked the mevalonate pathway to (i) geranylgeranyl pyrophosphate (GGPP)-mediated Rho GTPase activation and F-actin fiber assembly rather than the squalene/cholesterol arm of the mevalonate cascade, and (ii) reduction of YAP/TAZ inhibitory phosphorylation and sustained YAP/TAZ transcriptional activity via nuclear accumulation independent of canonical Hippo-LATS1/2 kinase activity. With the increasing evidence - including from our own laboratory - of aberrant YAP/TAZ activity in human TM cells isolated from glaucoma eyes or induced with glaucoma-associated stressors,15–22 in conjunction with the recent discovery of YAP as a potential “risk gene” for open-angle glaucoma23 that frequently involves impaired TM outflow function, we here tested the hypothesis that simvastatin attenuates glucocorticoid-induced glaucomatous TM cell pathobiology via targeting YAP/TAZ activity in a tissue-mimetic ECM microenvironment.46
Immune metabolism: a bridge of dendritic cells function
Published in International Reviews of Immunology, 2022
Yuting Sun, Liyu Zhou, Weikai Chen, Linhui Zhang, Hongbo Zeng, Yunxia Sun, Jun Long, Dongping Yuan
Cells increase intracellular cholesterol in two ways (Figure 3). Cholesterol is taken up through extracellular low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) [58], and synthesized in the ER [54]. Cholesterols can be ingested from serum LDL and VLDL, which are internalized through low-density lipoprotein receptor (LDLR) and very low-density lipoprotein receptor (VLDLR) on the cell surface. Cholesterol ester of LDL and VLDL is hydrolyzed in the lysosome and free cholesterol is released to the plasma membrane, which involves Niemann-Pick type C1 (NPC1) protein [58–61]. In addition, acetyl-CoA can be converted to cholesterol through mevalonate pathway including at least 20 enzymes [62]. All of the enzymes containing rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in ER are regulated by the sterol regulatory element-binding proteins (SREBPs) transcription factor family [63]. Cholesterol derived from ER can be transported to raft or non-raft microdomains on the plasma membrane via the Golgi. However, when secreted proteins are blocked from being transferred from the ER, most of the cholesterol bypasses the Golgi apparatus and reaches the cell membrane [64].
Therapeutic effect of statins on airway remodeling during asthma
Published in Expert Review of Respiratory Medicine, 2022
Mashael Alabed, Noha Mousaad Elemam, Rakhee K Ramakrishnan, Narjes Saheb Sharif-Askari, Tarek Kashour, Qutayba Hamid, Rabih Halwani
Statins are considerably one of the most efficient lipid-lowering medications. Their main mechanism of action is through the inhibition of the enzyme β-hydroxy β-methylglutaryl- coenzyme A (HMG-CoA) reductase, which controls the rate-limiting step in the synthesis of cholesterol. Statins inhibit the conversion of HMG-CoA to mevalonate via the mevalonate pathway. This will lead to a decrease in mevalonate’s metabolites including isoprenoids, such as isopentenyl diphosphate (IPP), farnesyl pyrophosphate (FPP), geranylgeranyl pyrophosphate (GGPP), and sterols, such as squalene and cholesterol. Isoprenoids represent crucial players in the regulation of small GTPases of the Rab, Rho, and Ras families. GTPases are recognized as key molecules that play a role in cell survival, proliferation, differentiation, and immune system regulation [32–34].