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Plant Molecular Biology Mar 1999
Review
Topics: Dimethylallyltranstransferase; Plant Proteins; Plants; Protein Prenylation
PubMed: 10344192
DOI: 10.1023/a:1006170020836 -
Nature Chemical Biology Oct 2006In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both... (Review)
Review
In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.
Topics: Animals; Antineoplastic Agents; Humans; Models, Molecular; Molecular Conformation; Progeria; Protein Prenylation; Proteins
PubMed: 16983387
DOI: 10.1038/nchembio818 -
Recent Progress in Hormone Research 1999Protein prenylation refers to a type of lipid modification in which either a 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid is linked via a thioether bond to... (Review)
Review
Protein prenylation refers to a type of lipid modification in which either a 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins. The majority of prenylated proteins belong to a group termed "CaaX proteins" that are defined by a specific C-terminal motif that directs their modification by this process. The ménage of CaaX-type prenylated proteins encompasses a wide variety of molecules that are found primarily at the cytoplasmic face of cellular membranes. These include nuclear lamins, Ras and a multitude of GTP-binding proteins (G proteins), several protein kinases and phosphatases, as well as other important proteins. A tremendous number of cellular signaling processes and regulatory events are under the control of CaaX prenyl proteins. While the attached isoprenoid lipids, in general, support the membrane association of the modified proteins, some proteins also clearly participate directly in protein-protein interactions. This chapter will emphasize 1) the biochemistry of the two enzymes termed farnesyltransferase and geranylgeranyltransferase type I, responsible for CaaX protein prenylation, and 2) biological roles for these modifications. Throughout, we will attempt to highlight the significance of prenylation in specific cellular events. The critical importance of this class of lipid modifications is attested to by the emergence of farnesyltransferase as a target for the development of anti-cancer therapeutics.
Topics: Alkyl and Aryl Transferases; Consensus Sequence; Farnesyltranstransferase; Humans; Protein Prenylation
PubMed: 10548882
DOI: No ID Found -
Journal of Inherited Metabolic Disease Sep 2012Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational... (Review)
Review
Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational modification is important for the maturation and processing of proteins. Both processes are necessary to mediate protein-protein and membrane-protein associations, in addition to regulating the localisation and function of proteins. The severe phenotype of animals deficient in enzymes involved in both prenylation and maturation highlights the significance of these processes. Moreover, alterations in the genes coding for isoprenylated proteins or enzymes that are involved in both prenylation and maturation processes have been found to be the basis of severe human diseases, such as cancer, neurodegenerative disorders, retinitis pigmentosa, and premature ageing syndromes. Recent studies on isoprenylation and postprenylation processing in pathological conditions have unveiled surprising aspects of these modifications and their roles in different cellular pathways. The identification of these enzymes as therapeutic targets has led researchers to validate their effects in vitro and in vivo as antitumour or antiageing agents. This review attempts to summarise the basic aspects of protein isoprenylation and postprenylation, integrating our data with that observed in other studies to provide a comprehensive scenario of progeroid syndromes and the therapeutic avenues.
Topics: Animals; Disease; Humans; Protein Prenylation; Proteins
PubMed: 22307208
DOI: 10.1007/s10545-011-9445-y -
Nature Reviews. Immunology May 2006Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that... (Review)
Review
Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.
Topics: Animals; Autoimmune Diseases; Drug Delivery Systems; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunologic Factors; Protein Prenylation
PubMed: 16639429
DOI: 10.1038/nri1839 -
Nature Reviews. Cancer Oct 2011Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming...
Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyl-transferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Cell Cycle; Cell Proliferation; Cell Survival; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Molecular Targeted Therapy; Monomeric GTP-Binding Proteins; Neoplasms; Neuropeptides; Protein Prenylation; Randomized Controlled Trials as Topic; Ras Homolog Enriched in Brain Protein; Signal Transduction
PubMed: 22020205
DOI: 10.1038/nrc3151 -
Current Cancer Drug Targets 2016The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine... (Review)
Review
The process of protein prenylation involves the covalent linkage of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoid lipds to conserved cysteine residues in the carboxyl-terminus of proteins. Protein geranylgeranyltransferase I (GGTase-I) is the enzyme that catalyzes the addition of the geranylgeranyl moiety from geranylgeranyl pyrophosphate to the target protein, which contains a Cterminal consensus sequence termed a CaaX motif. Geranylgeranylation is important to the function of a number of proteins, including the majority of Rho GTPases, G protein gamma subunits, and several other regulatory proteins. Studies over the past two decades have revealed that many of these proteins contribute to tumor development and metastasis. Blocking Rho GTPase activity through inhibition of GGTase-I in particular has been advanced as a potential strategy for disease therapy. This review will provide an overview of the CaaX prenyltransferases, the rationale for targeting GGTase-I in cancer in particular, and the current status of GGTase-I inhibitor (GGTI) development.
Topics: Alkyl and Aryl Transferases; Animals; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Protein Prenylation
PubMed: 26648485
DOI: 10.2174/1568009616666151203224603 -
Anti-cancer Agents in Medicinal... May 2012The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and... (Review)
Review
The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy.
Topics: Animals; Antineoplastic Agents; Cholesterol; Hedgehog Proteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mevalonic Acid; Neoplasms; Protein Prenylation; Signal Transduction
PubMed: 22413970
DOI: 10.2174/187152012800228715 -
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 -
MBio Apr 2024is a widespread intracellular protozoan pathogen infecting virtually all warm-blooded animals. This parasite acquires host-derived resources to support its replication...
is a widespread intracellular protozoan pathogen infecting virtually all warm-blooded animals. This parasite acquires host-derived resources to support its replication inside a membrane-bound parasitophorous vacuole within infected host cells. Previous research has discovered that actively endocytoses host proteins and transports them to a lysosome-equivalent structure for digestion. However, few molecular determinants required for trafficking of host-derived material within the parasite were known. A recent study (Q.-Q. Wang, M. Sun, T. Tang, D.-H. Lai, et al., mBio 14:e01309-23, 2023, https://doi.org/10.1128/mbio.01309-23) identified a critical role for membrane anchoring of proteins via prenylation in the trafficking of endocytosed host proteins by , including an essential ortholog of Rab1B. The authors also found that TgRab1 is crucial for protein trafficking of the rhoptry secretory organelles, indicating a dual role in endocytic and exocytic protein trafficking. This study sets the stage for further dissecting endomembrane trafficking in , along with potentially exploiting protein prenylation as a target for therapeutic development.
Topics: Animals; Toxoplasma; Protein Prenylation; Proteins; Organelles; Protein Transport
PubMed: 38407123
DOI: 10.1128/mbio.00283-24