Bisphosphate 3'-nucleotidase (BPNT1 in mammals and Met22/Hal2 in yeast) is one of five members of a family of signaling phosphatases united through a common tertiary structure and inhibition by subtherapeutic doses of the antibipolar drug lithium. Here we report a role for 3'-nucleotidase and its substrate, 3'-phosphoadenosine 5'-phosphate (PAP), in mediating the cellular effects of lithium. Lithium-induced inhibition of growth in yeast cells may be overcome by dose-dependent heterologous expression of human BPNT1. Disruption of the yeast 3'-nucleotidase gene or treatment of cells with lithium results in a >80-fold accumulation of PAP and leads to potent growth inhibition. These data indicate that the accumulation of a 3'-nucleotidase substrate, such as PAP, mediates the toxicity of lithium. To further probe this model we examined the growth inhibitory effects of lithium under conditions in which PAP biosynthetic machinery was concomitantly down-regulated. Disruption of met3 or met14 genes (ATP sulfurylase or phosphosulfate kinase), transcriptional down-regulation of MET3 through methionine addition, or administration of chlorate, a widely used cell-permeable sulfurylase inhibitor, function to reduce lithium-induced intracellular PAP accumulation and lithium toxicity; all of these effects were reversed by heterologous expression of human sulfurylase and kinase. Collectively, our data support a role for 3'-nucleotidase activity and PAP metabolism in aspects of lithium's mechanism of action and provide a platform for development of novel pharmacological modulators aimed at improving therapies for the treatment of bipolar disorder.
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Eur J Protistol
October 2023
Instituto de Bioquímica Médica Leopoldo de Meis (IBqM), UFRJ, Rio de Janeiro, RJ, Brazil.
Acanthamoeba castellanii is a free-living amoeba that acts as an opportunistic pathogen for humans and is the pathogenic agent of Acanthamoeba keratitis (AK). A. castellanii may present as proliferative and infective trophozoites or as resistant cysts during their life cycle.
View Article and Find Full Text PDFInt J Mol Sci
February 2023
Grupo de Enzimología, Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Medicina y Ciencias de la Salud, Universidad de Extremadura, 06006 Badajoz, Spain.
The gene is pro-virulent in avian pathogenic and in , where it encodes a periplasmic protein named CpdB. It is structurally related to cell wall-anchored proteins, CdnP and SntA, encoded by the also pro-virulent and genes of and , respectively. CdnP and SntA effects are due to extrabacterial hydrolysis of cyclic-di-AMP, and to complement action interference.
View Article and Find Full Text PDFEBioMedicine
December 2022
York Biomedical Research Institute, Department of Biology, University of York, United Kingdom. Electronic address:
Background: Miltefosine treatment failure in visceral leishmaniasis in Brazil has been associated with deletion of the miltefosine susceptibility locus (MSL) in Leishmania infantum. The MSL comprises four genes, 3'-nucleotidase/nucleases (NUC1 and NUC2); helicase-like protein (HLP); and 3,2-trans-enoyl-CoA isomerase (TEI).
Methods: In this study CRISPR-Cas9 was used to either epitope tag or delete NUC1, NUC2, HLP and TEI, to investigate their role in miltefosine resistance mechanisms.
Front Cell Infect Microbiol
August 2021
Medical Microbiology Research Group, CNC-Center for Neurosciences and Cell Biology, Coimbra, Portugal.
Host innate immunity is fundamental to the resistance against and infection, two of the most important agents contributing to human fungal infections. Phagocytic cells, such as neutrophils, constitute the first line of host defense mechanisms, and the release of neutrophil extracellular traps (NETs) represent an important strategy to immobilize and to kill invading microorganisms, arresting the establishment of infection. The purinergic system operates an important role in the homeostasis of immunity and inflammation, and ectophosphatase and ectonucleotidase activities are recognized as essential for survival strategies and infectious potential of several pathogens.
View Article and Find Full Text PDFTurkiye Parazitol Derg
June 2021
Ege Üniversitesi Tıp Fakültesi, Parazitoloji Anabilim Dalı, İzmir, Türkiye
Objective: This study aimed to determine the differences between the gene expression profiles of and promastigotes through comparative analysis of gene expressions.
Methods: Cell culture of (MHOM/IL/80) and (MHOM/MA/67/ITMAP/263) cell lines was performed. Afterwards, total RNA isolation and cDNA synthesis were performed and fold changes in the expression levels of 30 genes that play a role in metabolic pathways and nucleic acid synthesis and co-expressed in two species were evaluated by reverse transcriptase polymerase chain reaction.
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