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Journal of Peptide Science : An... Jan 2016Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale... (Review)
Review
Today, Fmoc SPPS is the method of choice for peptide synthesis. Very-high-quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications.
Topics: Amino Acids; Aspartic Acid; Cell Line; Epithelial Cells; Fluorenes; Glycosylation; Humans; Methylation; Peptides; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; Solid-Phase Synthesis Techniques
PubMed: 26785684
DOI: 10.1002/psc.2836 -
Biomedicine & Pharmacotherapy =... Aug 2023Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in... (Review)
Review
Prenyltransferases (PTases) are known to play a role in embryonic development, normal tissue homeostasis and cancer by posttranslationally modifying proteins involved in these processes. They are being discussed as potential drug targets in an increasing number of diseases, ranging from Alzheimer's disease to malaria. Protein prenylation and the development of specific PTase inhibitors (PTIs) have been subject to intense research in recent decades. Recently, the FDA approved lonafarnib, a specific farnesyltransferase inhibitor that acts directly on protein prenylation; and bempedoic acid, an ATP citrate lyase inhibitor that might alter intracellular isoprenoid composition, the relative concentrations of which can exert a decisive influence on protein prenylation. Both drugs represent the first approved agent in their respective substance class. Furthermore, an overwhelming number of processes and proteins that regulate protein prenylation have been identified over the years, many of which have been proposed as molecular targets for pharmacotherapy in their own right. However, certain aspects of protein prenylation, such as the regulation of PTase gene expression or the modulation of PTase activity by phosphorylation, have attracted less attention, despite their reported influence on tumor cell proliferation. Here, we want to summarize the advances regarding our understanding of the regulation of protein prenylation and the potential implications for drug development. Additionally, we want to suggest new lines of investigation that encompass the search for regulatory elements for PTases, especially at the genetic and epigenetic levels.
Topics: Protein Prenylation; Proteins; Dimethylallyltranstransferase; Enzyme Inhibitors; Terpenes; Prenylation
PubMed: 37236024
DOI: 10.1016/j.biopha.2023.114915 -
Molecules (Basel, Switzerland) Oct 2019Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental... (Review)
Review
Protein prenylation is one of the most important posttranslational modifications of proteins. Prenylated proteins play important roles in different developmental processes as well as stress responses in plants as the addition of hydrophobic prenyl chains (mostly farnesyl or geranyl) allow otherwise hydrophilic proteins to operate as peripheral lipid membrane proteins. This review focuses on selected aspects connecting protein prenylation with plant responses to both abiotic and biotic stresses. It summarizes how changes in protein prenylation impact plant growth, deals with several families of proteins involved in stress response and highlights prominent regulatory importance of prenylated small GTPases and chaperons. Potential possibilities of these proteins to be applicable for biotechnologies are discussed.
Topics: Biotechnology; Plant Proteins; Plants; Protein Prenylation; Stress, Physiological; Substrate Specificity
PubMed: 31671559
DOI: 10.3390/molecules24213906 -
Critical Reviews in Biochemistry and... Jun 2018The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery... (Review)
Review
The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein-protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer's disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed.
Topics: Alzheimer Disease; Animals; Dimethylallyltranstransferase; Heterotrimeric GTP-Binding Proteins; Humans; Protein Prenylation; Terpenes
PubMed: 29718780
DOI: 10.1080/10409238.2018.1458070 -
ACS Chemical Biology Jan 2015Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a... (Review)
Review
Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a geranylgeranyl isoprenoid. It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins. Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity. Here, we review the biochemistry of the prenyltransferase enzymes and numerous isoprenoid analogs synthesized to investigate various aspects of prenylation and prenyltransferases. We also give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases including cancers, progeria, aging, parasitic diseases, and bacterial and viral infections. Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.
Topics: Animals; Biotechnology; Dimethylallyltranstransferase; Enzyme Inhibitors; Humans; Protein Prenylation; Substrate Specificity; Terpenes; ras Proteins
PubMed: 25402849
DOI: 10.1021/cb500791f -
Cell Metabolism Dec 2020Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling...
Effector regulatory T (eT) cells are essential for immune tolerance and depend upon T cell receptor (TCR) signals for generation. The immunometabolic signaling mechanisms that promote the differentiation and maintenance of eT cells remain unclear. Here, we show that isoprenoid-dependent posttranslational lipid modifications dictate eT cell accumulation and function by intersecting with TCR-induced intracellular signaling. We find that isoprenoids are essential for activated T cell suppressive activity, and T cell-specific deletion of the respective farnesylation- and geranylgeranylation-promoting enzymes Fntb or Pggt1b leads to the development of fatal autoimmunity, associated with reduced eT cell accumulation. Mechanistically, Fntb promotes eT cell maintenance by regulating mTORC1 activity and ICOS expression. In contrast, Pggt1b acts as a rheostat of TCR-dependent transcriptional programming and Rac-mediated signaling for establishment of eT cell differentiation and immune tolerance. Therefore, our results identify bidirectional metabolic signaling, specifically between immunoreceptor signaling and metabolism-mediated posttranslational lipid modifications, for the differentiation and maintenance of eT cells.
Topics: Animals; Cell Differentiation; Female; Immune Tolerance; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Prenylation; T-Lymphocytes, Regulatory; Terpenes
PubMed: 33207246
DOI: 10.1016/j.cmet.2020.10.022 -
Science China. Life Sciences Apr 2015The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation... (Review)
Review
The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation and geranylgeranylation, using farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) as the substrate, respectively. The prenylation occurs by covalent addition of these two types of isoprenoids to cysteine residues at or near the carboxyl terminus of the proteins that possess CaaX motif, such as Ras small GTPase family. The attachment of hydrophobic prenyl groups can anchor the proteins to intracellular membranes and trigger downstream cell signaling pathway. Geranylgeranyl biphosphate synthase (GGPPS) catalyzes the synthesis of 20-carbon GGPP from 15-carbon FPP. The abnormal expression of this enzyme will affect the relative content of FPP and GGPP, and thus disrupts the balance between protein farnesylation and geranylgeranylation, which participates into various aspects of cellular physiology and pathology. In this paper, we mainly review the property of this important protein post-translational modification and research progress in its regulation of cigarette smoke induced pulmonary disease, adipocyte insulin sensitivity, the inflammation response of Sertoli cells, the hepatic lipogenesis and the cardiac hypertrophy.
Topics: Cardiomegaly; Diterpenes; Humans; Protein Prenylation
PubMed: 25862656
DOI: 10.1007/s11427-015-4836-1 -
Genome Biology 2003Three different protein prenyltransferases (farnesyltransferase and geranylgeranyltransferases I and II) catalyze the attachment of prenyl lipid anchors 15 or 20 carbons... (Review)
Review
Three different protein prenyltransferases (farnesyltransferase and geranylgeranyltransferases I and II) catalyze the attachment of prenyl lipid anchors 15 or 20 carbons long to the carboxyl termini of a variety of eukaryotic proteins. Farnesyltransferase and geranylgeranyltransferase I both recognize a 'Ca1a2X' motif on their protein substrates; geranylgeranyltransferase II recognizes a different, non-CaaX motif. Each enzyme has two subunits. The genes encoding CaaX protein prenyltransferases are considerably longer than those encoding non-CaaX subunits, as a result of longer introns. Alternative splice forms are predicted to occur, but the extent to which each splice form is translated and the functions of the different resulting isoforms remain to be established. Farnesyltransferase-inhibitor drugs have been developed as anti-cancer agents and may also be able to treat several other diseases. The effects of these inhibitors are complicated, however, by the overlapping substrate specificities of geranylgeranyltransferase I and farnesyltransferase.
Topics: Alkyl and Aryl Transferases; Amino Acid Motifs; Amino Acid Sequence; Animals; Catalysis; Evolution, Molecular; Farnesyltranstransferase; Humans; Models, Molecular; Molecular Sequence Data; Protein Prenylation; Rats; Sequence Alignment; Substrate Specificity
PubMed: 12702202
DOI: 10.1186/gb-2003-4-4-212 -
International Journal of Molecular... May 2022Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras... (Review)
Review
Protein prenylation is a post-translational modification controlling the localization, activity, and protein-protein interactions of small GTPases, including the Ras superfamily. This covalent attachment of either a farnesyl (15 carbon) or a geranylgeranyl (20 carbon) isoprenoid group is catalyzed by four prenyltransferases, namely farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), Rab geranylgeranyltransferase (GGTase-II), and recently discovered geranylgeranyltransferase type III (GGTase-III). Blocking small GTPase activity, namely inhibiting prenyltransferases, has been proposed as a potential disease treatment method. Inhibitors of prenyltransferase have resulted in substantial therapeutic benefits in various diseases, such as cancer, neurological disorders, and viral and parasitic infections. In this review, we overview the structure of FTase, GGTase-I, GGTase-II, and GGTase-III and summarize the current status of research on their inhibitors.
Topics: Carbon; Dimethylallyltranstransferase; Farnesyltranstransferase; Protein Prenylation; Terpenes
PubMed: 35628237
DOI: 10.3390/ijms23105424 -
Molecular Neurobiology Aug 2014Protein prenylation is an important lipid posttranslational modification of proteins. It includes protein farnesylation and geranylgeranylation, in which the 15-carbon... (Review)
Review
Protein prenylation is an important lipid posttranslational modification of proteins. It includes protein farnesylation and geranylgeranylation, in which the 15-carbon farnesyl pyrophosphate or 20-carbon geranylgeranyl pyrophosphate is attached to the C-terminus of target proteins, catalyzed by farnesyl transferase or geranylgeranyl transferases, respectively. Protein prenylation facilitates the anchoring of proteins into the cell membrane and mediates protein-protein interactions. Among numerous proteins that undergo prenylation, small GTPases represent the largest group of prenylated proteins. Small GTPases are involved in regulating a plethora of cellular functions including synaptic plasticity. The prenylation status of small GTPases determines the subcellular locations and functions of the proteins. Dysregulation or dysfunction of small GTPases leads to the development of different types of disorders. Emerging evidence indicates that prenylated proteins, in particular small GTPases, may play important roles in the pathogenesis of Alzheimer's disease. This review focuses on the prenylation of Ras and Rho subfamilies of small GTPases and its relation to synaptic plasticity and Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Humans; Neuronal Plasticity; Neurons; Protein Prenylation; Protein Processing, Post-Translational; ras Proteins; rho GTP-Binding Proteins
PubMed: 24390573
DOI: 10.1007/s12035-013-8627-z