Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.
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http://dx.doi.org/10.1016/j.molcel.2019.01.028 | DOI Listing |
PLoS One
November 2022
Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agricultural and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of Chinese Academy of Agricultural Sciences, Lanzhou, China.
AMPK can activate nicotinamide phosphoribosyltransferase (NAMPT), increasing the ratio of oxidized nicotinamide adenine dinucleotide (NAD+)/reduced nicotinamide adenine dinucleotide (NADH) ratio, leading to the activation of the energy receptor SIRT1. This pathway is known as the AMPK/SIRT1 signaling pathway. SIRT1 deacetylates and activate LKB1, which is activated by phosphorylation of AMPK (Thr172) and inhibited by phosphorylase-mediated dephosphorylation of AMPK.
View Article and Find Full Text PDFJ Biol Chem
December 2022
Institute of Cytology, Russian Academy of Sciences, St Petersburg, Russia. Electronic address:
Nicotinamide riboside (NR) is an effective precursor of nicotinamide adenine dinucleotide (NAD) in human and animal cells. NR supplementation can increase the level of NAD in various tissues and thereby improve physiological functions that are weakened or lost in experimental models of aging or various human pathologies. However, there are also reports questioning the efficacy of NR supplementation.
View Article and Find Full Text PDFBrain Struct Funct
November 2022
Department of Anatomy and Neurobiology, School of Basic Medicine, Shandong University, Jinan, 250012, Shandong, China.
Drug memory is associated with drug-taking experience and environmental cues, which mainly contribute to addiction. Recent studies report that glycogenolysis-derived lactate from astrocyte transport to neurons is necessary for long-term potentiation and memory formation instead of its function as an energy substrate. However, the role of astrocyte-neuron lactate transfer in neuronal plasticity and methamphetamine (METH)-induced addiction memory consolidation and retrieval, especially the underlying mechanisms, are not clear.
View Article and Find Full Text PDFKorean J Physiol Pharmacol
July 2022
Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia.
There is a paucity of detailed data related to the effect of senescence on the mitochondrial antioxidant capacity and redox state of senescent human cells. Activities of TCA cycle enzymes, respiratory chain complexes, hydrogen peroxide (HO), superoxide anions (SA), lipid peroxides (LPO), protein carbonyl content (PCC), thioredoxin reductase 2 (TrxR2), superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPx1), glutathione reductase (GR), reduced glutathione (GSH), and oxidized glutathione (GSSG), along with levels of nicotinamide cofactors and ATP content were measured in young and senescent human foreskin fibroblasts. Primary and senescent cultures were biochemically identified by monitoring the augmented cellular activities of key glycolytic enzymes including phosphofructokinase, lactate dehydrogenase, and glycogen phosphorylase, and accumulation of HO, SA, LPO, PCC, and GSSG.
View Article and Find Full Text PDFBMC Pharmacol Toxicol
February 2022
Department of Occupational Health and Environmental Health, Public Health College of Xinjiang Medical University, No.567, Sunde North Road, Shuimogou District, Xinjiang, 830011, Urumqi, People's Republic of China.
Background: Arsenic metabolism enzymes can affect the toxic effects of arsenic. However, the effects of different genders on the metabolites and metabolic enzymes in liver arsenic metabolism is still unclear. This study analyzed the gender differences of various arsenic metabolites and metabolic enzymes and further explored the effects of gender differences on arsenic metabolism in liver tissues of rats.
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