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Current Opinion in Plant Biology Oct 2019In flowering plants, extensive male-female interactions during pollen germination on the stigma, pollen tube growth and guidance in the transmitting tract, and pollen... (Review)
Review
In flowering plants, extensive male-female interactions during pollen germination on the stigma, pollen tube growth and guidance in the transmitting tract, and pollen tube reception by the female gametophyte are required for successful double fertilization in which various signaling cascades are involved. Peptide/receptor-like kinase-mediated signaling has been found playing important roles in these male-female interactions. Here, we mainly summarized the progress made on the regulatory roles of peptide/receptor-like kinase-mediated signaling pathways in four critical stages during reproduction in higher plants.
Topics: Female; Male; Ovule; Phosphotransferases; Pollen Tube; Pollination; Signal Transduction
PubMed: 30999163
DOI: 10.1016/j.pbi.2019.03.004 -
Digestive and Liver Disease : Official... Aug 2019
Topics: Humans; Lipids; Liver; Liver Diseases, Alcoholic; Phosphotransferases (Alcohol Group Acceptor); Sphingosine
PubMed: 31031176
DOI: 10.1016/j.dld.2019.04.002 -
Journal of Biomolecular Structure &... 2023Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs... (Review)
Review
Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs because of genetic alterations, and the molecular insights suggest that the accumulation of mutation in the individual drug target genes is the primary mechanism of multi-drug resistant tuberculosis. Chorismate is an essential structural fragment for the synthesis of aromatic amino acids and synthesized biochemically by a number of bacteria, including Mycobacterium tuberculosis, utilizing the shikimate pathway. This shikimate kinase is the newer possible target for the generation of novel antitubercular drug because this pathway is expressed only in mycobacterium and not in Mammals. The discovery and development of shikimate kinase inhibitors provide an opportunity for the development of novel selective medications. Multiple shikimate kinase inhibitors have been identified via virtual screening and related protein-ligand interactions along with their studies. These inhibitors bind to the active site in a similar fashion to shikimate. In the current review, we present an overview of the biology and chemistry of the shikimate kinase protein and its inhibitors, with special emphasis on the various active scaffold against the enzyme. A variety of chemically diversified synthetic scaffolds including Benzothiazoles, Oxadiazoles, Thiobarbiturates, Naphthoquinones, Thiazoleacetonitriles, Hybridized Pyrazolone derivatives, Orthologous biological macromolecule derivatives, Manzamine Alkaloids derivatives, Dipeptide inhibitor, and Chalcones are discussed in detail. These derivatives bind to the specific target appropriately proving their potential ability through different binding interactions and effectively explored as an effective and selective Sk inhibitor.Communicated by Ramaswamy H. Sarma.
Topics: Animals; Shikimic Acid; Antitubercular Agents; Mycobacterium tuberculosis; Phosphotransferases (Alcohol Group Acceptor); Enzyme Inhibitors; Mammals
PubMed: 36974959
DOI: 10.1080/07391102.2023.2193985 -
Autophagy Sep 2023Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained...
Although PIKFYVE phosphoinositide kinase inhibitors can selectively eliminate PIKFYVE-dependent human cancer cells and , the basis for this selectivity has remained elusive. Here we show that the sensitivity of cells to the PIKFYVE inhibitor WX8 is not linked to PIKFYVE expression, macroautophagic/autophagic flux, the BRAF mutation, or ambiguous inhibitor specificity. PIKFYVE dependence results from a deficiency in the PIP5K1C phosphoinositide kinase, an enzyme required for conversion of phosphatidylinositol-4-phosphate (PtdIns4P) into phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P/PIP2), a phosphoinositide associated with lysosome homeostasis, endosome trafficking, and autophagy. PtdIns(4,5)P is produced via two independent pathways. One requires PIP5K1C; the other requires PIKFYVE and PIP4K2C to convert PtdIns3P into PtdIns(4,5)P. In PIKFYVE-dependent cells, low concentrations of WX8 specifically inhibit PIKFYVE , thereby increasing the level of its substrate PtdIns3P while suppressing PtdIns(4,5)P synthesis and inhibiting lysosome function and cell proliferation. At higher concentrations, WX8 inhibits both PIKFYVE and PIP4K2C , which amplifies these effects to further disrupt autophagy and induce cell death. WX8 did not alter PtdIns4P levels. Consequently, inhibition of PIP5K1C in WX8-resistant cells transformed them into sensitive cells, and overexpression of PIP5K1C in WX8-sensitive cells increased their resistance to WX8. This discovery suggests that PIKFYVE-dependent cancers could be identified clinically by low levels of PIP5K1C and treated with PIKFYVE inhibitors. DMSO: dimethylsulfoxide; ELISA: enzyme-linked immunosorbent assay; LC3-I: microtubule associated protein light chain 3-I; LC3-II: microtubule associated protein light chain 3-II; MS: mass spectrometry; PtdIns: phosphatidylinositol; PtdIns3P: PtdIns-3-phosphate; PtdIns4P: PtdIns-4-phosphate; PtdIns5P: PtdIns-5-phosphate; PtdIns(3,5)P: PtdIns-3,5-bisphosphate; PtdIns(4,5)P/PIP2: PtdIns-4,5-bisphosphate; PtdIns(3,4,5)P/PIP3: PtdIns-3,4,5-trisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PI4KA: phosphatidylinositol 4-kinase alpha; PI4KB: phosphatidylinositol 4-kinase beta; PI4K2A: phosphatidylinositol 4-kinase type 2 alpha; PI4K2B: phosphatidylinositol 4-kinase type 2 beta; PIP4K2A: phosphatidylinositol-5-phosphate 4-kinase type 2 alpha; PIP4K2B: phosphatidylinositol-5-phosphate 4-kinase type 2 beta; PIP4K2C: phosphatidylinositol-5-phosphate 4-kinase type 2 gamma; PIP5K1A: phosphatidylinositol-4-phosphate 5-kinase type 1 alpha; PIP5K1B: phosphatidylinositol-4-phosphate 5-kinase type 1 beta; PIP5K1C: phosphatidylinositol-4-phosphate 5-kinase type 1 gamma; WX8: 1H-indole-3-carbaldehyde (4-anilino-6-[4-morpholinyl]-1,3,5-triazin-2-yl)hydrazone.
Topics: Humans; 1-Phosphatidylinositol 4-Kinase; Autophagy; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phosphatidylinositols; Microtubule-Associated Proteins; Neoplasms; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36803256
DOI: 10.1080/15548627.2023.2182594 -
Advances in Biological Regulation Jan 2022Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are a group of central eukaryotic metabolites and signaling molecules. Due to the diverse cellular functions and... (Review)
Review
Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are a group of central eukaryotic metabolites and signaling molecules. Due to the diverse cellular functions and widespread diseases InsPs and PP-InsPs are associated with, pharmacological targeting of the kinases involved in their biosynthesis has become a significant research interest in the last decade. In particular, the development of inhibitors for inositol hexakisphosphate kinases (IP6Ks) has leaped forward, while other inositol phosphate kinases have received scant attention. This review summarizes the efforts undertaken so far for discovering potent and selective inhibitors for this diverse group of small molecule kinases. The benefits of pharmacological inhibition are highlighted, given the multiple kinase-independent functions of inositol phosphate kinases. The distinct structural families of InsP and PP-InsP kinases are presented, and we discuss how compound availability for different inositol phosphate kinase families varies drastically. Lead compound discovery and optimization for the inositol kinases would benefit from detailed structural information on the ATP-binding sites of these kinases, as well as reliable biochemical and cellular read-outs to monitor inositol phosphate kinase activity in complex settings. Efforts to further tune well-established inhibitors, while simultaneously reviving tool compound development for the more neglected kinases from this family are indisputably worthwhile, considering the large potential therapeutic benefits.
Topics: Diphosphates; Eukaryotic Cells; Humans; Inositol Phosphates; Phosphorylation; Phosphotransferases (Phosphate Group Acceptor); Signal Transduction
PubMed: 34802993
DOI: 10.1016/j.jbior.2021.100836 -
Science Advances Apr 2023Cells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase...
Cells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase FERONIA (FER), which is a proposed cell wall sensor, modulates phosphatidylserine plasma membrane accumulation and nano-organization, a key regulator of Rho GTPase signaling in Arabidopsis. We demonstrate that FER is required for both Rho-of-Plant 6 (ROP6) nano-partitioning at the membrane and downstream production of reactive oxygen species upon hyperosmotic stimulus. Genetic and pharmacological rescue experiments indicate that phosphatidylserine is required for a subset of, but not all, FER functions. Furthermore, application of FER ligand shows that its signaling controls both phosphatidylserine membrane localization and nanodomains formation, which, in turn, tunes ROP6 signaling. Together, we propose that a cell wall-sensing pathway controls via the regulation of membrane phospholipid content, the nano-organization of the plasma membrane, which is an essential cell acclimation to environmental perturbations.
Topics: Arabidopsis Proteins; Phosphatidylserines; Signal Transduction; Arabidopsis; Phosphotransferases; Cell Membrane; Plants
PubMed: 37027473
DOI: 10.1126/sciadv.add4791 -
Current Opinion in Chemical Biology Jun 2023Eukaryotes depend upon the proper localization, accumulation, and release of intracellular Ca2+. This is regulated through specialized cellular compartments, signaling... (Review)
Review
Eukaryotes depend upon the proper localization, accumulation, and release of intracellular Ca2+. This is regulated through specialized cellular compartments, signaling pathways, and Ca2+-binding proteins and channels. Cytosolic and extracellular signaling governing intracellular Ca2+ stores are well explored. However, regulatory signals within Ca2+ storage organelles like the endoplasmic/sarcoplasmic reticulum are not well understood. This is due to a lack of identified signaling molecules - like protein kinases - within these compartments, limited information on their regulation, and incomplete understanding of mechanisms involving modified substrates. Here we review recent advances in intralumenal signaling focusing on the secretory pathway protein kinase FAM20C and its regulation, Ca2+-binding protein substrates, and potential mechanisms through which FAM20C may regulate Ca2+ storage.
Topics: Sarcoplasmic Reticulum; Calcium; Secretory Pathway; Endoplasmic Reticulum; Phosphotransferases
PubMed: 36966700
DOI: 10.1016/j.cbpa.2023.102279 -
Frontiers in Immunology 2023Secretory pathway kinase or kinase-like proteins (SPKKPs) are effective in the lumen of the endoplasmic reticulum (ER), Golgi apparatus (GA), and extracellular space.... (Review)
Review
Secretory pathway kinase or kinase-like proteins (SPKKPs) are effective in the lumen of the endoplasmic reticulum (ER), Golgi apparatus (GA), and extracellular space. These proteins are involved in secretory signaling pathways and are distinctive from typical protein kinases. Various reports have shown that SPKKPs regulate the tumorigenesis and progression of human cancer the phosphorylation of various substrates, which is essential in physiological and pathological processes. Emerging evidence has revealed that the expression of SPKKPs in human cancers is regulated by multiple factors. This review summarizes the current understanding of the contribution of SPKKPs in tumorigenesis and the progression of immunity. With the epidemic trend of immunotherapy, targeting SPKKPs may be a novel approach to anticancer therapy. This study briefly discusses the recent advances regarding SPKKPs.
Topics: Humans; Carcinogenesis; Neoplasms; Phosphotransferases; Proteins; Secretory Pathway; Signal Transduction; Disease Progression
PubMed: 36825005
DOI: 10.3389/fimmu.2023.942849 -
ELife Dec 2022How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here, we investigated how glycolytic flux impacts embryonic development,...
How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here, we investigated how glycolytic flux impacts embryonic development, using presomitic mesoderm (PSM) patterning as the experimental model. First, we identified fructose 1,6-bisphosphate (FBP) as an in vivo sentinel metabolite that mirrors glycolytic flux within PSM cells of post-implantation mouse embryos. We found that medium-supplementation with FBP, but not with other glycolytic metabolites, such as fructose 6-phosphate and 3-phosphoglycerate, impaired mesoderm segmentation. To genetically manipulate glycolytic flux and FBP levels, we generated a mouse model enabling the conditional overexpression of dominant active, cytoplasmic PFKFB3 (cytoPFKFB3). Overexpression of cytoPFKFB3 indeed led to increased glycolytic flux/FBP levels and caused an impairment of mesoderm segmentation, paralleled by the downregulation of Wnt-signaling, reminiscent of the effects seen upon FBP-supplementation. To probe for mechanisms underlying glycolytic flux-signaling, we performed subcellular proteome analysis and revealed that cytoPFKFB3 overexpression altered subcellular localization of certain proteins, including glycolytic enzymes, in PSM cells. Specifically, we revealed that FBP supplementation caused depletion of Pfkl and Aldoa from the nuclear-soluble fraction. Combined, we propose that FBP functions as a flux-signaling metabolite connecting glycolysis and PSM patterning, potentially through modulating subcellular protein localization.
Topics: Animals; Mice; Mesoderm; Glycolysis; Embryonic Development; Embryo, Mammalian; Wnt Signaling Pathway; Phosphotransferases
PubMed: 36469462
DOI: 10.7554/eLife.83299 -
Chemical Communications (Cambridge,... Nov 2019DNA-encoded library (DEL) screening has emerged as an important method for early stage drug and probe molecule discovery. The vast majority of screens using DELs have... (Review)
Review
DNA-encoded library (DEL) screening has emerged as an important method for early stage drug and probe molecule discovery. The vast majority of screens using DELs have been relatively simple binding assays. The library is incubated with a target molecule, which is almost always a protein, and the DNAs that remain associated with the target after thorough washing are amplified and deep sequenced to reveal the chemical structures of the ligands they encode. Recently however, a number of different screening formats have been introduced that demand more than simple binding. These include a format that demands hits exhibit high selectivity for target vs. off-targets, a protocol to screen for enzyme inhibitors and another to identify organocatalysts in a DEL. These and other novel assay formats are reviewed in this article. We also consider some of the most significant remaining challenges in DEL assay development.
Topics: Drug Discovery; Enzyme Inhibitors; Gene Library; Humans; Ligands; Membrane Proteins; Peptide Library; Phosphotransferases; Protein Binding
PubMed: 31633708
DOI: 10.1039/c9cc06256d