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Philosophical Transactions of the Royal... Apr 1992Heterotrimeric GTP-dependent regulatory proteins (G-proteins) mediate modulation by many cell surface receptors. Activation of the G-proteins promotes dissociation of... (Review)
Review
Heterotrimeric GTP-dependent regulatory proteins (G-proteins) mediate modulation by many cell surface receptors. Activation of the G-proteins promotes dissociation of their alpha and beta gamma subunits. The similarity of behaviour of beta gamma subunits derived from a variety of G-proteins has led to their use as affinity reagents for the analysis of the more unique alpha subunits. The evolution of these uses is presented. One of the more insightful results was the isolation of a new class of G-protein alpha subunits (the alpha q subfamily) which have been shown to regulate the activity of a phospholipase C (PLC) specific for phosphatidylinositols. The experimental evidence leading to this conclusion is discussed. The activation by alpha q increases the apparent Vmax of the beta isoform of phosphatidylinositol-specific phospholipase C (PLC beta) and can be modulated by beta gamma subunits.
Topics: Animals; GTP-Binding Proteins; Hydrolysis; Kinetics; Lipid Metabolism; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Type C Phospholipases
PubMed: 1351294
DOI: 10.1098/rstb.1992.0041 -
Journal of Biomolecular Structure &... Mar 2023is the causative agent of leishmaniasis, responsible for social and economic disruption, especially in developing countries. Lack of effective drugs with few side...
is the causative agent of leishmaniasis, responsible for social and economic disruption, especially in developing countries. Lack of effective drugs with few side effects have necessitated the discovery of newer therapeutic solutions for leishmaniasis. Glycophosphatidylinositol (GPI) synthesis plays a vital role in protozoan cell membranes structural formation and antigenic modification. Hence, any disruption in its biosynthesis can prove fatal to the parasitic protozoans. N-acetylglucosamine-phosphatidylinositol de-N-acetylase (NAGP-deacetylase) is an enzyme from the GPI biosynthetic pathway that catalyzes the deacetylation of N-acetylglucosaminylphosphatidylinositol to glucosaminylphosphatidylinositol, a step essential for the proper functioning of the enzyme. In the quest for novel scaffolds as anti-leishmaniasis agents, we have executed virtual screening, density function theory, molecular dynamics and MM-GBSA based energy calculations with a natural product library and a diverse library set from Chembridge database. Two compounds, 14671 and 4610, were identified at the enzyme's active site and interacted with catalytic residues, Asp43, Asp44, His41, His147, His 150, Arg80 and Arg231. Both molecules exhibited stable conformation in their protein-ligand complexes with binding free energies for compound-14671 and compound-4610 of -54 ± 4 and -50 ± 4 kcal/mol, respectively. These scaffolds can be incorporated in future synthetic determinations, focusing on developing druggable inhibitor support, increasing potency, and introducing species selectivity.Communicated by Ramaswamy H. Sarma.
Topics: Leishmania donovani; Acetylesterase; Phosphatidylinositols; Acetylglucosamine; Molecular Dynamics Simulation; Molecular Docking Simulation
PubMed: 35014594
DOI: 10.1080/07391102.2021.2025429 -
The Journal of Biological Chemistry Jan 1990
Review
Topics: Cell Membrane; Fatty Acids; Glycolipids; Glycosylphosphatidylinositols; Humans; Molecular Conformation; Phosphatidylinositols
PubMed: 2136848
DOI: No ID Found -
Cell Calcium Oct 1982
Comparative Study Review
Topics: Animals; Anti-Bacterial Agents; Calcium; Erythrocytes; In Vitro Techniques; Liver; Muscles; Nerve Tissue; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Rats; Salivary Glands; Steroids; Synaptosomes
PubMed: 6297743
DOI: 10.1016/0143-4160(82)90031-8 -
Chemistry (Weinheim An Der Bergstrasse,... Jan 2020Phosphatidylinositol (PI) is the biosynthetic precursor for seven phosphoinositides, important signaling lipids in cells. A membrane-permeant caged PI derivative...
Phosphatidylinositol (PI) is the biosynthetic precursor for seven phosphoinositides, important signaling lipids in cells. A membrane-permeant caged PI derivative featuring a photo-removable coumarinyl group masking the negative charge of the phosphate, as well as two enzymatically removable butyrate esters for increased lipophilicity and for preventing phosphate migration, were synthesized. Rapid cell entry and cellular labeling in fixed cells was demonstrated by a photo-cross-linkable diazirine followed by attachment of a fluorophore through click chemistry. Using this technique, we found that the multifunctional caged PI derivative resided predominantly at internal membranes but rapidly changed to the plasma membrane after uncaging. Accordingly, a preliminary proteomic analysis of the lipid-protein conjugates revealed that the two major PI transport proteins PITPα and β were prime targets of the photo-cross-linked PI derivative.
Topics: Cell Membrane; Click Chemistry; HeLa Cells; Humans; Microscopy, Fluorescence; Phosphatidylinositols; Staining and Labeling
PubMed: 31550056
DOI: 10.1002/chem.201903704 -
Advances in Experimental Medicine and... 2023Cell membranes regulate a wide range of phenomena that are implicated in key cellular functions. Cholesterol, a critical component of eukaryotic cell membranes, is...
Cell membranes regulate a wide range of phenomena that are implicated in key cellular functions. Cholesterol, a critical component of eukaryotic cell membranes, is responsible for cellular organization, membrane elasticity, and other critical physicochemical parameters. Besides cholesterol, other lipid components such as phosphatidylinositol 4,5-bisphosphate (PIP2) are found in minor concentrations in cell membranes yet can also play a major regulatory role in various cell functions. In this chapter, we describe how solid-state deuterium nuclear magnetic resonance (H NMR) spectroscopy together with neutron spin-echo (NSE) spectroscopy can inform synergetic changes to lipid molecular packing due to cholesterol and PIP2 that modulate the bending rigidity of lipid membranes. Fundamental structure-property relations of molecular self-assembly are illuminated and point toward a length and time-scale dependence of cell membrane mechanics, with significant implications for biological activity and membrane lipid-protein interactions.
Topics: Phosphatidylinositols; Cell Membrane; Membrane Lipids; Cholesterol; Biophysics; Lipid Bilayers; Phosphatidylinositol 4,5-Diphosphate
PubMed: 36988877
DOI: 10.1007/978-3-031-21547-6_2 -
Journal of Cell Science Jun 2001
Topics: Inositol Phosphates; Models, Biological; Phosphatidylinositols; Phosphorylation; Second Messenger Systems; Substrate Specificity
PubMed: 11493657
DOI: 10.1242/jcs.114.12.2207 -
The Biochemical Journal May 1987
Review
Topics: Glycolipids; Glycosides; Glycosylphosphatidylinositols; Inositol; Membrane Proteins; Models, Chemical; Peptides; Phosphatidylinositols; Protein Conformation; Protein Precursors
PubMed: 2959270
DOI: 10.1042/bj2440001 -
Proceedings of the National Academy of... Aug 2016The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to...
The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish type I kinase PIP5Kα, we identified a structural motif unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas residues flanking the phosphate binding Arg244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how PIPKs achieve their exquisite substrate specificity.
Topics: Animals; Binding Sites; Crystallography, X-Ray; Models, Molecular; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Binding; Protein Domains; Substrate Specificity; Zebrafish Proteins
PubMed: 27439870
DOI: 10.1073/pnas.1522112113 -
Current Biology : CB Sep 1995Newly revealed properties of phosphatidylinositol transfer protein help to explain the cellular targeting of lipids involved in signal transduction, and indicate that... (Review)
Review
Newly revealed properties of phosphatidylinositol transfer protein help to explain the cellular targeting of lipids involved in signal transduction, and indicate that inositol lipids play a part in directing membrane traffic.
Topics: Carrier Proteins; Cell Membrane; Humans; Lipid Metabolism; Membrane Proteins; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phospholipid Transfer Proteins; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 8542291
DOI: 10.1016/s0960-9822(95)00196-5