Keeping the balance in NAD metabolism

Strømland, Øyvind; Niere, Marc; Aa, Nikiforov; VanLinden, Magali R.; Heiland, Ines; Ziegler, Mathias

doi:10.1042/bst20180417

Cited by 62 publications

(47 citation statements)

References 110 publications

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Section: Discussionmentioning

confidence: 99%

“…The NAD + levels play important signaling roles in eukaryotes by regulating processes such as DNA repair, cell cycle regulation, gene expression and calcium signaling (6,39). Impaired biosynthesis and increased NAD + consumption are associated with aging and pathologies in mammals (39). The use of NAD + as a substrate for a range of enzyme prokaryotic enzymes, including those involved in RNA modification (40), sirtuins (41) and ADP-ribosylation (42), suggest that NAD + also play important regulatory roles in prokaryotes.…”

Section: Discussionmentioning

confidence: 99%

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NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling

Santos

Gerhardt

Parize

et al. 2020

Journal of Biological Chemistry

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Nicotinamideadenine dinucleotide (NAD + ) is a central metabolite participating in core metabolic redox reactions. The prokaryotic NAD synthetase enzyme NadE catalyzes the last step of NAD + biosynthesis, converting nicotinic acid adenine dinucleotide (NaAD) to NAD + . Some members of the NadE family use L-glutamine as a nitrogen donor and are named NadE Gln . Previous gene neighborhood analysis has indicated that the bacterial nadE gene is frequently clustered with the gene encoding the regulatory signal transduction protein PII, suggesting a functional relationship between these proteins in response to the nutritional status and the carbon/nitrogen ratio of the bacterial cell. Here, using affinity chromatography, bioinformatics analyses, NAD synthetase activity and biolayer interferometry assays, we show that PII and NadE Gln physically interact in vitro, that this complex relieves NadE Gln negative feedback inhibition by NAD + . This mechanism is conserved in distantly related bacteria. Of note, the PII protein allosteric effector and cellular nitrogen level indicator 2-oxoglutarate (2-OG) inhibited the formation of the PII-NadE Gln complex within a physiological range. These results indicate an interplay between the levels of ATP, ADP, 2-OG, PII-sensed glutamine, and NAD + , representing a metabolic hub that may balance the levels of core nitrogen and carbon metabolites. Our findings support the notion that PII proteins act as a dissociable regulatory subunit of NadE Gln , thereby enabling the control of NAD + biosynthesis according to the nutritional status of the bacterial cell. https://www.jbc.org/cgi/

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling

Santos

Gerhardt

Parize

et al. 2020

Journal of Biological Chemistry

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“…Therefore, it is the balance between NAD ? cleavage and synthesis that dictates the total intracellular NAD pool, and by extension, cellular metabolism and protein acetylation status (Strømland et al 2019).…”

Section: Nicotinamide Adenine Dinucleotide (Nad)mentioning

confidence: 99%

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

Sedlackova

Korolchuk

2020

Biogerontology

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Cellular adaptation to various types of stress requires a complex network of steps that altogether lead to reconstitution of redox balance, degradation of damaged macromolecules and restoration of cellular metabolism. Advances in our understanding of the interplay between cellular signalling and signal translation paint a complex picture of multilayered paths of regulation. In this review we explore the link between cellular adaptation to metabolic and oxidative stresses by activation of autophagy, a crucial cellular catabolic pathway. Metabolic stress can lead to changes in the redox state of nicotinamide adenine dinucleotide (NAD), a co-factor in a variety of enzymatic reactions and thus trigger autophagy that acts to sequester intracellular components for recycling to support cellular growth. Likewise, autophagy is activated by oxidative stress to selectively recycle damaged macromolecules and organelles and thus maintain cellular viability. Multiple proteins that help regulate or execute autophagy are targets of posttranslational modifications (PTMs) that have an effect on their localization, binding affinity or enzymatic activity. These PTMs include acetylation, a reversible enzymatic modification of a protein's lysine residues, and oxidation, a set of reversible and irreversible modifications by free radicals. Here we highlight the latest findings and outstanding questions on the interplay of autophagy with metabolic stress, presenting as changes in NAD levels, and oxidative stress, with a focus on autophagy proteins that are regulated by both, oxidation and acetylation. We further explore the relevance of this multi-layered signalling to healthy human ageing and their potential role in human disease.

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“…It has become apparent that altered NAD + metabolism is correlated with several metabolic disorders and diseases, and therapeutic approaches by modulation of the NAD + biosynthetic and consuming pathways using NAD + precursors or chemical inhibitors are being actively explored [134][135][136][137]. Changes in NAD + metabolism affect many cellular processes either through redox metabolism or activities of NAD + -consuming enzymes.…”

Section: Nad + and Diseasesmentioning

confidence: 99%

NAD+ Metabolism and Regulation: Lessons From Yeast

2020

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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite involved in various cellular processes. The cellular NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD+ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD+ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD+ metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD+ homeostasis factors. These findings help provide a molecular basis for how may NAD+ and NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD+ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD+ homeostasis, and regulation of NAD+ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD+ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD+ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD+ homeostasis. These studies may also contribute to the development of effective NAD+-based therapeutic strategies specific for different types of NAD+ deficiency related disorders.

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Keeping the balance in NAD metabolism

Cited by 62 publications

References 110 publications

NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling

NAD+ biosynthesis in bacteria is controlled by global carbon/nitrogen levels via PII signaling

The crosstalk of NAD, ROS and autophagy in cellular health and ageing

NAD+ Metabolism and Regulation: Lessons From Yeast

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