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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 -
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 -
Trends in Cancer Jun 2021The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered... (Review)
Review
The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.
Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease Models, Animal; Diterpenes; Farnesyltranstransferase; Feeding Behavior; Food-Drug Interactions; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Metabolic Networks and Pathways; Mevalonic Acid; Mice; Neoplasms; Pinocytosis; Polyisoprenyl Phosphates; Prenylation
PubMed: 33358111
DOI: 10.1016/j.trecan.2020.11.008 -
Journal of Natural Medicines Jun 2020Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for... (Review)
Review
Aromatic prenyltransferases (PTases), including ABBA-type and dimethylallyl tryptophan synthase (DMATS)-type enzymes from bacteria and fungi, play important role for diversification of the natural products and improvement of the biological activities. For a decade, the characterization of enzymes and enzymatic synthesis of prenylated compounds by using ABBA-type and DMATS-type PTases have been demonstrated. Here, I introduce several examples of the studies on chemoenzymatic synthesis of unnatural prenylated compounds and the enzyme engineering of ABBA-type and DMATS-type PTases.
Topics: Alkyl and Aryl Transferases; Bacteria; Biological Products; Dimethylallyltranstransferase; Fungi; Prenylation; Protein Engineering
PubMed: 32180104
DOI: 10.1007/s11418-020-01393-x -
PloS One 2022Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids...
Protein prenylation by farnesyltransferase (FTase) is often described as the targeting of a cysteine-containing motif (CaaX) that is enriched for aliphatic amino acids at the a1 and a2 positions, while quite flexible at the X position. Prenylation prediction methods often rely on these features despite emerging evidence that FTase has broader target specificity than previously considered. Using a machine learning approach and training sets based on canonical (prenylated, proteolyzed, and carboxymethylated) and recently identified shunted motifs (prenylation only), this study aims to improve prenylation predictions with the goal of determining the full scope of prenylation potential among the 8000 possible Cxxx sequence combinations. Further, this study aims to subdivide the prenylated sequences as either shunted (i.e., uncleaved) or cleaved (i.e., canonical). Predictions were determined for Saccharomyces cerevisiae FTase and compared to results derived using currently available prenylation prediction methods. In silico predictions were further evaluated using in vivo methods coupled to two yeast reporters, the yeast mating pheromone a-factor and Hsp40 Ydj1p, that represent proteins with canonical and shunted CaaX motifs, respectively. Our machine learning-based approach expands the repertoire of predicted FTase targets and provides a framework for functional classification.
Topics: Alkyl and Aryl Transferases; Farnesyltranstransferase; Machine Learning; Protein Prenylation; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 35749383
DOI: 10.1371/journal.pone.0270128 -
Nature Communications Feb 2019Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low...
Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low natural abundance, alternative production methods are needed. Metabolic engineering enables natural product biosynthesis from inexpensive biomass, but is limited by the complexity of secondary metabolite pathways, intermediate and product toxicities, and substrate accessibility. Alternatively, enzyme catalyzed prenyl transfer provides excellent regio- and stereo-specificity, but requires expensive isoprenyl pyrophosphate substrates. Here we develop a flexible cell-free enzymatic prenylating system that generates isoprenyl pyrophosphate substrates from glucose to prenylate an array of natural products. The system provides an efficient route to cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA) at >1 g/L, and a single enzymatic step converts the precursors into cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA). Cell-free methods may provide a powerful alternative to metabolic engineering for chemicals that are hard to produce in living organisms.
Topics: Biological Products; Cannabinoids; Fungal Proteins; Gas Chromatography-Mass Spectrometry; Metabolic Engineering; Molecular Structure; Prenylation; Substrate Specificity
PubMed: 30718485
DOI: 10.1038/s41467-019-08448-y -
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 -
Current Opinion in Chemical Biology Dec 2018Prenylated flavin (prFMN) is a recently discovered cofactor that underpins catalysis in the ubiquitous microbial UbiDX system. UbiX acts as a flavin prenyltransferase... (Review)
Review
Prenylated flavin (prFMN) is a recently discovered cofactor that underpins catalysis in the ubiquitous microbial UbiDX system. UbiX acts as a flavin prenyltransferase while UbiD is a prFMN-dependent reversible (de)carboxylase. The extensive modification of flavin by prenylation, and the consecutive oxidation to the prFMN azomethine ylide, leads to cofactor metamorphosis. While prFMN is no longer able to perform N5-based classical flavin chemistry, it is capable of forming cycloadducts with dipolarophiles, long-lived C4a-based radical species as well as undergoing extensive light driven isomerization. An ever-expanding range of distinct prFMN forms hints at the possibility of novel prFMN driven biochemistry yet to be discovered.
Topics: Aspergillus niger; Carboxy-Lyases; Escherichia coli; Flavins; Models, Molecular; Oxidation-Reduction; Prenylation; Pseudomonas aeruginosa
PubMed: 30326424
DOI: 10.1016/j.cbpa.2018.09.024 -
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 -
Small GTPases Mar 2018Rab GTPases, the highly conserved members of Ras GTPase superfamily are central players in the vesicular trafficking. They are critically involved in intracellular... (Review)
Review
Rab GTPases, the highly conserved members of Ras GTPase superfamily are central players in the vesicular trafficking. They are critically involved in intracellular trafficking pathway, beginning from formation of vesicles on donor membranes, defining trafficking specificity to facilitating vesicle docking on target membranes. Given the dynamic roles of Rabs during different stages of vesicular trafficking, mechanisms for their spatial and temporal regulation are crucial for normal cellular function. Regulation of Rab GTPase activity, localization and function has always been focused in and around the association of GDP dissociation inhibitor (GDI), Guanine nucleotide Exchange Factor (GEFs) and GTPase accelerating protein (GAP) to Rabs. However, several recent studies have highlighted the importance of different post-translational modifications in regulation of Rab activation and function. This review provides a summary of various post translational modifications (PTMs) and their significance to regulate localization and function of different Rabs.
Topics: Adenosine Monophosphate; Humans; Phosphorylation; Protein Prenylation; Protein Processing, Post-Translational; rab GTP-Binding Proteins
PubMed: 28426288
DOI: 10.1080/21541248.2017.1299270