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Molecular Neurobiology Dec 2016Isoprenylation is a posttranslational modification that transfers farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) to cysteine residues of a... (Review)
Review
Isoprenylation is a posttranslational modification that transfers farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) to cysteine residues of a particular set of proteins, causing their localization to the plasma membrane and other cellular compartments and so rendering them biologically active. Such a modification process, catalyzed by protein prenyltransferase including farnesyltransferase (FT), geranylgeranyltransferase I (GGTI), and geranylgeranyltransferase II (GGTII), is required for the transforming activity of many oncogenic proteins, including some RAS family members. In the past three decades, prenyltransferase has been extensively studied as a promising cancer therapeutic target in vitro, in animal models, and in the clinic. Recently, a growing number of studies suggest that prenyltransferases and the substrates FPP and GGPP also play fundamental roles in nervous system development and brain disorders. However, a systemic review about the advances of prenyltransferases in the field of neuroscience is lacking so far. Herein, we give a brief introduction for the structure and distribution of GGTI and comprehensively updated the recent advances of GGTI in neuronal dendritogenesis/synaptogenesis and in learning/memory-related behavioral performance. More importantly, we discussed the involvement of GGTI and its substrate GGPP in neurodegenerative disorders, such as aging, Alzheimer's disease, multiple sclerosis, and Niemann-Pick disease type C. The role of FT-FPP and GGTII is mentioned as well to compare with GGTI in these physiological and pathological processes. We hope that this systematical review about what we know about GGTI research in the brain can stimulate further studies on the underlying mechanism of GGTI-mediated isoprenylation in the pathogenesis of neurodegenerative and neurodevelopmental disorders.
Topics: Aging; Alkyl and Aryl Transferases; Animals; Brain; Dendrites; Humans; Neurogenesis; Protein Prenylation
PubMed: 26666664
DOI: 10.1007/s12035-015-9594-3 -
Accounts of Chemical Research Feb 2015CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions... (Review)
Review
CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions will facilitate the design of novel catalysts that can produce high quality compounds that can be employed, for example, as fuels and life saving drugs. We have used molecular dynamics (MD) methods and combined quantum mechanical/molecular mechanical (QM/MM) methods to study a series of proteins either whose substrates are too far away from the catalytic center or whose experimentally resolved substrate binding modes cannot explain the observed product distribution. In particular, we describe studies of farnesyl transferase (FTase) where the farnesyl pyrophosphate (FPP) substrate is ∼8 Å from the zinc-bound peptide in the active site of FTase. Using MD and QM/MM studies, we explain how the FPP substrate spans the gulf between it and the active site, and we have elucidated the nature of the transition state (TS) and offered an alternate explanation of experimentally observed kinetic isotope effects (KIEs). Our second story focuses on the nature of substrate dynamics in the aromatic prenyltransferase (APTase) protein NphB and how substrate dynamics affects the observed product distribution. Through the examples chosen we show the power of MD and QM/MM methods to provide unique insights into how protein substrate dynamics affects catalytic efficiency. We also illustrate how complex these reactions are and highlight the challenges faced when attempting to design de novo catalysts. While the methods used in our previous studies provided useful insights, several clear challenges still remain. In particular, we have utilized a semiempirical QM model (self-consistent charge density functional tight binding, SCC-DFTB) in our QM/MM studies since the problems we were addressing required extensive sampling. For the problems illustrated, this approach performed admirably (we estimate for these systems an uncertainty of ∼2 kcal/mol), but it is still a semiempirical model, and studies of this type would benefit greatly from more accurate ab initio or DFT models. However, the challenge with these methods is to reach the level of sampling needed to study systems where large conformational changes happen in the many nanoseconds to microsecond time regimes. Hence, how to couple expensive and accurate QM methods with sophisticated sampling algorithms is an important future challenge especially when large-scale studies of catalyst design become of interest. The use of MD and QM/MM models to elucidate enzyme catalytic pathways and to design novel catalytic agents is in its infancy but shows tremendous promise. While this Account summarizes where we have been, we also discuss briefly future directions that improve our fundamental ability to understand enzyme catalysis.
Topics: Farnesyltranstransferase; Molecular Dynamics Simulation; Protein Prenylation; Quantum Theory
PubMed: 25539152
DOI: 10.1021/ar500321u -
CaaX-motif-adjacent residues influence G protein gamma (Gγ) prenylation under suboptimal conditions.The Journal of Biological Chemistry Nov 2023Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including...
Prenylation is an irreversible post-translational modification that supports membrane interactions of proteins involved in various cellular processes, including migration, proliferation, and survival. Dysregulation of prenylation contributes to multiple disorders, including cancers and vascular and neurodegenerative diseases. Prenyltransferases tether isoprenoid lipids to proteins via a thioether linkage during prenylation. Pharmacological inhibition of the lipid synthesis pathway by statins is a therapeutic approach to control hyperlipidemia. Building on our previous finding that statins inhibit membrane association of G protein γ (Gγ) in a subtype-dependent manner, we investigated the molecular reasoning for this differential inhibition. We examined the prenylation of carboxy-terminus (Ct) mutated Gγ in cells exposed to Fluvastatin and prenyl transferase inhibitors and monitored the subcellular localization of fluorescently tagged Gγ subunits and their mutants using live-cell confocal imaging. Reversible optogenetic unmasking-masking of Ct residues was used to probe their contribution to prenylation and membrane interactions of the prenylated proteins. Our findings suggest that specific Ct residues regulate membrane interactions of the Gγ polypeptide, statin sensitivity, and extent of prenylation. Our results also show a few hydrophobic and charged residues at the Ct are crucial determinants of a protein's prenylation ability, especially under suboptimal conditions. Given the cell and tissue-specific expression of different Gγ subtypes, our findings indicate a plausible mechanism allowing for statins to differentially perturb heterotrimeric G protein signaling in cells depending on their Gγ-subtype composition. Our results may also provide molecular reasoning for repurposing statins as Ras oncogene inhibitors and the failure of using prenyltransferase inhibitors in cancer treatment.
Topics: Humans; Amino Acid Motifs; Drug Resistance; HeLa Cells; Heterotrimeric GTP-Binding Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Molecular; Mutation; Protein Prenylation; Protein Structure, Tertiary; Protein Transport; Signal Transduction
PubMed: 37739036
DOI: 10.1016/j.jbc.2023.105269 -
Small GTPases Mar 2018Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. Their activity can be tightly controlled within cells: Regulated by guanine... (Review)
Review
Rab proteins are the major regulators of vesicular trafficking in eukaryotic cells. Their activity can be tightly controlled within cells: Regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), they switch between an active GTP-bound state and an inactive GDP-bound state, interacting with downstream effector proteins only in the active state. Additionally, they can bind to membranes via C-terminal prenylated cysteine residues and they can be solubilized and shuttled between membranes by chaperone-like molecules called GDP dissociation inhibitors (GDIs). In this review we give an overview of Rab proteins with a focus on the current understanding of their regulation by GEFs, GAPs and GDI.
Topics: Amino Acid Sequence; Animals; Cell Membrane; GTPase-Activating Proteins; Guanine Nucleotide Dissociation Inhibitors; Guanine Nucleotide Exchange Factors; Humans; Protein Prenylation; rab GTP-Binding Proteins
PubMed: 28055292
DOI: 10.1080/21541248.2016.1276999 -
Chembiochem : a European Journal of... Sep 2022Regioselective carbon-carbon bond formation belongs to the challenging tasks in organic synthesis. In this context, C-C bond formation catalyzed by...
Regioselective carbon-carbon bond formation belongs to the challenging tasks in organic synthesis. In this context, C-C bond formation catalyzed by 4-dimethylallyltryptophan synthases (4-DMATSs) represents a possible tool to regioselectively synthesize C4-prenylated indole derivatives without site-specific preactivation and circumventing the need of protection groups as used in chemical synthetic approaches. In this study, a toolbox of 4-DMATSs to produce a set of 4-dimethylallyl tryptophan and indole derivatives was identified. Using three wild-type enzymes as well as variants, various C5-substituted tryptophan derivatives as well as N-methyl tryptophan were successfully prenylated with conversions up to 90 %. Even truncated tryptophan derivatives like tryptamine and 3-indole propanoic acid were regioselectively prenylated in position C4. The acceptance of C5-substituted tryptophan derivatives was improved up to 5-fold by generating variants (e. g. T108S). The feasibility of semi-preparative prenylation of selected tryptophan derivatives was successfully demonstrated on 100 mg scale at 15 mM substrate concentration, allowing to reduce the previously published multistep chemical synthetic sequence to just a single step.
Topics: Biocatalysis; Carbon; Dimethylallyltranstransferase; Indoles; Prenylation; Substrate Specificity; Tryptophan
PubMed: 35770709
DOI: 10.1002/cbic.202200311 -
Organic Letters Apr 2022Prenylation can impart pharmacological advantages to bioactive compounds. Global genome mining for prenylated cyclodipeptides identified a BGC from 132 containing a...
Prenylation can impart pharmacological advantages to bioactive compounds. Global genome mining for prenylated cyclodipeptides identified a BGC from 132 containing a cyclodipeptide synthase and two prenyltransferase genes. Subsequent heterologous expression allowed isolation and characterization of griseocazines, which displayed potent neuroprotective activity. Further biotransformation analyses revealed that prenyltransferases GczB and GczC catalyzed the stereospecific prenylation of cWW and attached geranyl and farnesyl groups to a cyclodipeptide scaffold, respectively.
Topics: Dimethylallyltranstransferase; Prenylation; Substrate Specificity
PubMed: 35436125
DOI: 10.1021/acs.orglett.2c00745 -
Natural Product Reports Dec 2021Covering: up to July 2020Naturally occurring chalcones carrying up to three modified or unmodified C-, C-, and C-prenyl moieties on both rings A and B as well as at the... (Review)
Review
Covering: up to July 2020Naturally occurring chalcones carrying up to three modified or unmodified C-, C-, and C-prenyl moieties on both rings A and B as well as at the α- and β-carbons are widely distributed in plants of the families of Fabaceae, Moraceae, Zingiberaceae and Cannabaceae. Xanthohumol and isobavachalcone being the most investigated representatives, exhibit diverse and remarkable biological and pharmacological activities. The present review deals with their structural characters, biological activities and occurrence in the plant kingdom. Biosynthesis of prenylated chalcones and metabolism of xanthohumol are also discussed.
Topics: Biological Products; Chalcones; Molecular Structure; Plants; Prenylation
PubMed: 33972962
DOI: 10.1039/d0np00083c -
Human Molecular Genetics Aug 2023Phosphodiesterase-6 (PDE6) is the key phototransduction effector enzyme residing in the outer segment (OS) of photoreceptors. Cone PDE6 is a tetrameric protein...
Phosphodiesterase-6 (PDE6) is the key phototransduction effector enzyme residing in the outer segment (OS) of photoreceptors. Cone PDE6 is a tetrameric protein consisting of two inhibitory subunits (γ') and two catalytic subunits (α'). The catalytic subunit of cone PDE6 contains a C-terminus prenylation motif. Deletion of PDE6α' C-terminal prenylation motif is linked to achromatopsia (ACHM), a type of color blindness in humans. However, mechanisms behind the disease and roles for lipidation of cone PDE6 in vision are unknown. In this study, we generated two knock-in mouse models expressing mutant variants of cone PDE6α' lacking the prenylation motif (PDE6α'∆C). We find that the C-terminal prenylation motif is the primary determinant for the association of cone PDE6 protein with membranes. Cones from PDE6α'∆C homozygous mice are less sensitive to light, and their response to light is delayed, whereas cone function in heterozygous PDE6α'∆C/+ mice is unaffected. Surprisingly, the expression level and assembly of cone PDE6 protein were unaltered in the absence of prenylation. Unprenylated assembled cone PDE6 in PDE6α'∆C homozygous animals is mislocalized and enriched in the cone inner segment and synaptic terminal. Interestingly, the disk density and the overall length of cone OS in PDE6α'∆C homozygous mutants are altered, highlighting a novel structural role for PDE6 in maintaining cone OS length and morphology. The survival of cones in the ACHM model generated in this study bodes well for gene therapy as a treatment option for restoring vision in patients with similar mutations in the PDE6C gene.
Topics: Humans; Mice; Animals; Cyclic Nucleotide Phosphodiesterases, Type 6; Retinal Cone Photoreceptor Cells; Light Signal Transduction; Prenylation
PubMed: 37384398
DOI: 10.1093/hmg/ddad108 -
Methods in Molecular Biology (Clifton,... 2015During the three decades of cell-penetrating peptides era the superfamily of CPPs has rapidly expanded, and the quest for new sequences continues. CPPs have been well...
During the three decades of cell-penetrating peptides era the superfamily of CPPs has rapidly expanded, and the quest for new sequences continues. CPPs have been well recognized by scientific community and they have been used for transduction of a wide variety of molecules and particles into cultured cells and in vivo. In parallel with application of CPPs for delivering of active payloads, the mechanisms that such peptides take advantage of for gaining access to cells' insides have been in the focus of intense studies. Although the common denominator "cell penetration" unites all CPPs, the interaction partners on the cell surface, evoked cellular responses and even the uptake mechanisms might greatly vary between different peptide types. Here we present some possibilities for classification of CPPs based on their type of origin, physical-chemical properties, and the extent of modifications and design efforts. We also briefly analyze the internalization mechanisms with regard to their classification into groups based on physical-chemical characteristics.
Topics: Animals; Cations; Cell Membrane; Cell-Penetrating Peptides; Fatty Acids; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Prenylation
PubMed: 26202259
DOI: 10.1007/978-1-4939-2806-4_1 -
Journal of Molecular and Cellular... Jan 2020Cardiovascular disease (CVD) is one of the most threatening diseases to human health and life, and the number of patients is increasing year by year. Thus, it is of... (Review)
Review
Cardiovascular disease (CVD) is one of the most threatening diseases to human health and life, and the number of patients is increasing year by year. Thus, it is of great significance to study the pathogenesis, prevention and treatment of CVDs. The occurrence and development of CVDs involve dynamic, complex and delicate intracellular processes and the pathogenesis is not entirely clear. In contrast to genetic mutations, most of the protein post-translational modifications (PTMs) are reversible, and can affect the activity, stability, subcellular localization, protein-protein interaction etc., of the substrate targets, emerging as key mediators of a number of CVD progression. Under pathological conditions, the PTMs undergo aberrant balances which cause changes of the substrate target proteins in expression level, localization and capacity to activate downstream signaling pathways. Therefore, new approaches can be created aiming to correct the abnormal PTM alterations in treating CVDs. This review summarizes some of the more recent advances in PTMs, focusing on SUMOylation, neddylation, succinylation, and prenylation, and the effect of these modifications on cardiovascular function and progression, which may provide potential targets for future therapeutics.
Topics: Animals; Cardiovascular Diseases; Humans; Prenylation; Protein Processing, Post-Translational; Succinic Acid; Sumoylation; Ubiquitination
PubMed: 31751566
DOI: 10.1016/j.yjmcc.2019.11.146