Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Pehar, Mariana; Harlan, Benjamin A.; Killoy, Kelby M.; Vargas, Marcelo R.

doi:10.1089/ars.2017.7145

Cited by 60 publications

(43 citation statements)

References 196 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of both NMA1 and NMA2 suppresses proteotoxicity in yeast models of polyglutamine and α-synuclein-induced neurodegeneration by targeting toxic misfolded proteins for degradation [25]. This supports the neuroprotective role that human Nmnats play in axon degeneration and neurodegenerative diseases [5,26,27].…”

Section: Introductionsupporting

confidence: 56%

“…Cells must properly balance NAD + biosynthesis with its consumption in order to maintain optimal cellular function. Moreover, abnormalities in NAD + metabolism have been associated with a number of metabolic disorders and disease [3][4][5][6]. Understanding the regulation of NAD + homeostasis may help elucidate the mechanisms of these disorders.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

View full text Add to dashboard Cite

ABSTRACTNAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are not completely understood. We previously identified the N-terminal (Nt) protein acetyltransferase complex NatB as a NAD+ homeostasis factor. Cells lacking NatB show an approximate 50% reduction in the NAD+ level and aberrant metabolism of NAD+ precursors, which are associated with a decrease of nicotinamide mononucleotide adenylyltransferases (Nmnat) protein levels. Here we show this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins, and not other NatB substrates. Nt-acetylation is a critical regulator of protein degradation by the N-end rule pathways, indicating absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats does not significantly differ from Nt-acetylated Nmnats, suggesting reduced Nmnat levels in NmatB mutants are not due to increased post-translational degradation of non-Nt-acetylated Nmnats. In line with these observations, deletion or depletion of N-rule pathway ubiquitin E3 ligases in NatB mutants is not sufficient to restore NAD+ levels. Moreover, the status of Nt-acetylation does not alter the rate of translation initiation of Nmnats. Collectively our studies suggest absence of Nt-acetylation may increase co-translational degradation of nascent Nmnat polypeptides, which results in reduced Nmnat levels in NatB mutants. Nmnat activities are essential for all routes of NAD+ biosynthesis. Understanding the regulation of Nmnat protein homeostasis will facilitate our understanding of the molecular basis and regulation of NAD+ metabolism.

show abstract

Section: Introductionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Because of the breadth of cellular processes regulated by these enzymes, it is through this co‐substrate role that fluctuations in NAD + can majorly influence the modulation of transcriptional events, signalling pathways and enzyme kinetics to coordinate changes in metabolic flux with appropriate physiological responses . This review complements the existing literature in the area, with a focus on describing pathways involved in the regulation of NAD + homeostasis, in addition to providing an overview of how changes in NAD + metabolism may be targeted to treat various diseases.…”

Section: Introductionmentioning

confidence: 99%

NAD⁺: A key metabolic regulator with great therapeutic potential

Sultani

Samsudeen

Osborne

et al. 2017

J Neuroendocrinology

View full text Add to dashboard Cite

+) is a ubiquitous metabolite that serves an essential role in the catabolism of nutrients. Recently, there has been a surge of interest in NAD + biology, with the recognition that NAD + influences many biological processes beyond metabolism, including transcription, signalling and cell survival.There are a multitude of pathways involved in the synthesis and breakdown of ).This redox cycling of NAD + is a key process across numerous metabolic pathways (eg, glycolysis, oxidative phosphorylation).By contrast to its redox role where the levels of NAD + stay essentially constant, NAD + has more recently gained attention following recognition that it also functions as a co-substrate for a range of different enzymes, including sirtuins, poly(ADP-ribose) polymerases (PARPs) and cyclic ADP-ribose synthases, where NAD + is actively degraded during the enzymatic processes catalysed by these proteins.Because of the breadth of cellular processes regulated by these en- | NAD + HOMEOSTASISThe 11The main pathways involved in the biosynthesis of NAD + are the Preiss-Handler pathway, the de novo biosynthesis pathway and

show abstract

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Cited by 60 publications

References 196 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

NAD+ Metabolism and Regulation: Lessons From Yeast

NAD⁺: A key metabolic regulator with great therapeutic potential

Contact Info

Product

Resources

About

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Cited by 60 publications

References 196 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

NAD+ Metabolism and Regulation: Lessons From Yeast

NAD+: A key metabolic regulator with great therapeutic potential

Contact Info

Product

Resources

About

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

NAD⁺: A key metabolic regulator with great therapeutic potential