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Platelets Dec 2023Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase...
Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time ( < .005) and attenuated clot firmness ( < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV ( < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control ( < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.
Topics: Humans; Adenosine Diphosphate; Atorvastatin; Blood Platelets; Fibrinogen; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Prenylation; rab GTP-Binding Proteins; rap1 GTP-Binding Proteins; Thrombosis
PubMed: 37139869
DOI: 10.1080/09537104.2023.2206921 -
Journal of Integrative Neuroscience Mar 2022Alzheimer's disease (AD) is a neurodegeneration csharacterized by amyloid-β (Aβ) deposition and abnormally phosphorylated Tau protein aggregation. Autophagy, as an... (Review)
Review
Alzheimer's disease (AD) is a neurodegeneration csharacterized by amyloid-β (Aβ) deposition and abnormally phosphorylated Tau protein aggregation. Autophagy, as an important cellular metabolic activity, is closely related to the production, secretion and clearance of Aβ peptide and Tau phosphorylation level. Therefore, autophagy may become a potential target for AD treatment. A large number of molecules are involved in the mammalian target of rapamycin (mTOR)-dependent or mTOR-independent pathway of autophagy. More and more evidences show that statins can intervene autophagy by regulating the activity or expression level of autophagy-related proteins and genes. On the one hand, statins can induce autophagy through Sirtuin1 (SIRT1), P21, nuclear P53 and adenylate activated protein kinase (AMPK). On the other hand, statins inhibit the mevalonate metabolism pathway, thereby interfering with the prenylation of small GTPases, leading to autophagy dysfunction. Statins can also reduce the levels of LAMP2 and dynein, destroying autophagy. In this review, we focused on the role of autophagy in AD and the autophagy mechanism of statins in the potential treatment of AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Autophagy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Signal Transduction
PubMed: 35364634
DOI: 10.31083/j.jin2102046 -
The Journal of Biological Chemistry Oct 2023Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic...
Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic mechanisms governing oocyte development regulated by metabolic enzymes remain largely unknown. Our investigation demonstrates that geranylgeranyl diphosphate synthase1 (Ggps1), the crucial enzyme in the mevalonate pathway responsible for synthesizing isoprenoid metabolite geranylgeranyl pyrophosphate from farnesyl pyrophosphate, is essential for oocyte maturation in mice. Our findings reveal that the deletion of Ggps1 that prevents protein prenylation in fully grown oocytes leads to subfertility and offspring metabolic defects without affecting follicle development. Oocytes that lack Ggps1 exhibit disrupted mitochondrial homeostasis and the mitochondrial defects arising from oocytes are inherited by the fetal offspring. Mechanistically, the excessive farnesylation of mitochondrial ribosome protein, Dap3, and decreased levels of small G proteins mediate the mitochondrial dysfunction induced by Ggps1 deficiency. Additionally, a significant reduction in Ggps1 levels in oocytes is accompanied by offspring defects when females are exposed to a high-cholesterol diet. Collectively, this study establishes that mevalonate pathway-protein prenylation is vital for mitochondrial function in oocyte maturation and provides evidence that the disrupted protein prenylation resulting from an imbalance between farnesyl pyrophosphate and geranylgeranyl pyrophosphate is the major mechanism underlying impairment of oocyte quality induced by high cholesterol.
PubMed: 37611828
DOI: 10.1016/j.jbc.2023.105183 -
Small GTPases Mar 2018Rab molecular switches are key players in defining membrane identity and regulating intracellular trafficking events in eukaryotic cells. In spite of their global... (Review)
Review
Rab molecular switches are key players in defining membrane identity and regulating intracellular trafficking events in eukaryotic cells. In spite of their global structural similarity, Rab-family members acquired particular features that allow them to perform specific cellular functions. The overall fold and local sequence conservations enable them to utilize a common machinery for prenylation and recycling; while individual Rab structural differences determine interactions with specific partners such as GEFs, GAPs and effector proteins. These interactions orchestrate the spatiotemporal regulation of Rab localization and their turning ON and OFF, leading to tightly controlled Rab-specific functionalities such as membrane composition modifications, recruitment of molecular motors for intracellular trafficking, or recruitment of scaffold proteins that mediate interactions with downstream partners, as well as actin cytoskeleton regulation. In this review we summarize structural information on Rab GTPases and their complexes with protein partners in the context of partner binding specificity and functional outcomes of their interactions in the cell.
Topics: Amino Acid Sequence; Animals; Conserved Sequence; Humans; Protein Binding; rab GTP-Binding Proteins
PubMed: 28632484
DOI: 10.1080/21541248.2017.1336191 -
International Journal of Molecular... Jul 2015The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with... (Review)
Review
The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.
Topics: Autophagy; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonate Kinase Deficiency; Mevalonic Acid; Mitochondria; Phosphotransferases (Alcohol Group Acceptor); Protein Prenylation; TOR Serine-Threonine Kinases
PubMed: 26184189
DOI: 10.3390/ijms160716067 -
Magyar Onkologia Sep 2020KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma (LADC) in the western countries. Although the different mutations of the KRAS gene... (Review)
Review
KRAS mutations are the most common gain-of-function alterations in lung adenocarcinoma (LADC) in the western countries. Although the different mutations of the KRAS gene have been identified decades ago, the development of drugs targeting the KRAS protein directly have not been successful due to the lack of small molecule binding sites and the extremely high affinity to cellular GTP. Indirect strategies to inhibit KRAS (e.g. inhibitors of farnesyltransferase, prenylation, synthetic lethal partners and KRAS downstream signaling) have so far also failed. In recent times, however several compounds have been developed that target subtype- specific KRAS mutations. Covalent KRAS G12C-specific inhibitors showed the most promising preclinical results. Below, we summarize the predictive and prognostic value of KRAS mutations in LADC as well as the current targeting strategies.
Topics: Adenocarcinoma of Lung; Humans; Lung Neoplasms; Mutation; Prognosis; Proto-Oncogene Proteins p21(ras)
PubMed: 33196710
DOI: No ID Found -
BioRxiv : the Preprint Server For... Oct 2023Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin...
Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.
PubMed: 37961667
DOI: 10.1101/2023.10.23.563509 -
Journal of Internal Medicine Aug 2020The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are... (Review)
Review
The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRAS , there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRAS inhibitor that possesses favourable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRAS and inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits the in vivo growth of multiple KRAS -mutant cell line xenografts, causes tumour regression in patient-derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant-specific lung and colorectal cancer. In this review, we discuss the history of RAS drug-targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long-awaited opportunity to selectively target mutant KRAS in patients.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Mutation; Neoplasms; Protein Prenylation; Proto-Oncogene Proteins p21(ras)
PubMed: 32176377
DOI: 10.1111/joim.13057 -
The New Phytologist Jan 2015Membranes have long been known to act as more than physical barriers within and between plant cells. Trafficking of membrane proteins, signalling from and across... (Review)
Review
Membranes have long been known to act as more than physical barriers within and between plant cells. Trafficking of membrane proteins, signalling from and across membranes, organisation of membranes and transport through membranes are all essential processes for plant cellular function. These processes rely on a myriad array of proteins regulated in a variety of manners and are frequently required to be directly associated with membranes. For integral membrane proteins, the mode of membrane association is readily apparent, but many peripherally associated membrane proteins are outwardly soluble proteins. In these cases the proteins are frequently modified by the addition of lipids allowing direct interaction with the hydrophobic core of membranes. These modifications include N-myristoylation, S-acylation (palmitoylation), prenylation and GPI anchors but until recently little was truly known about their function in plants. New data suggest that these modifications are able to act as more than just membrane anchors, and dynamic S-acylation in particular is emerging as a means of regulating protein function in a similar manner to phosphorylation. This review discusses how these modifications occur, their impact on protein function, how they are regulated, recent advances in the field and technical approaches for studying these modifications.
Topics: Acylation; Lipid Metabolism; Lipoproteins; Membrane Microdomains; Membrane Proteins; Models, Biological; Plant Proteins; Plants; Prenylation; Protein Processing, Post-Translational; Protein Transport
PubMed: 25283240
DOI: 10.1111/nph.13085 -
Journal of Food and Drug Analysis Jan 2017Furanocoumarins are a specific group of secondary metabolites that commonly present in higher plants, such as citrus plants. The major furanocoumarins found in... (Review)
Review
Furanocoumarins are a specific group of secondary metabolites that commonly present in higher plants, such as citrus plants. The major furanocoumarins found in grapefruits (Citrus paradisi) include bergamottin, epoxybergamottin, and 6',7'-dihydroxybergamottin. During biosynthesis of these furanocoumarins, coumarins undergo biochemical modifications corresponding to a prenylation reaction catalyzed by the cytochrome P450 enzymes with the subsequent formation of furan rings. Because of undesirable interactions with several medications, many studies have developed methods for grapefruit furanocoumarin quantification that include high-performance liquid chromatography coupled with UV detector or mass spectrometry. The distribution of furanocoumarins in grapefruits is affected by several environmental conditions, such as processing techniques, storage temperature, and packing materials. In the past few years, grapefruit furanocoumarins have been demonstrated to exhibit several biological activities including antioxidative, -inflammatory, and -cancer activities as well as bone health promotion both in vitro and in vivo. Notably, furanocoumarins potently exerted antiproliferative activities against cancer cell growth through modulation of several molecular pathways, such as regulation of the signal transducer and activator of transcription 3, nuclear factor-κB, phosphatidylinositol-3-kinase/AKT, and mitogen-activated protein kinase expression. Therefore, based on this review, we suggest furanocoumarins may serve as bioactive components that contribute, at least in part, to the health benefits of grapefruit.
Topics: Citrus paradisi; Furocoumarins; Humans; Mitogen-Activated Protein Kinases
PubMed: 28911545
DOI: 10.1016/j.jfda.2016.11.008