Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. VOLUME 284 (2009) PAGES 158-164

Belenky, Peter; Christensen, Kathryn C.; Gazzaniga, Francesca S.; Pletnev, Alexandre A.; Brenner, Charles

doi:10.1016/s0021-9258(20)32533-3

Cited by 20 publications

(32 citation statements)

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“…Once in the cytosol, NR can be phosphorylated by NR kinases (NRKs) to produce NMN (135). Cells are also capable of using NR in an NRKindependent way, in which the purine nucleoside phosphorylase (PNP) generates NAM that enters the salvage pathway (21).…”

Section: Synthesismentioning

confidence: 99%

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Pehar

Harlan

Killoy

et al. 2018

Antioxidants & Redox Signaling

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Section: Synthesismentioning

confidence: 99%

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Pehar

Harlan

Killoy

et al. 2018

Antioxidants & Redox Signaling

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“…We initially tested several natural or artificial pyridine ribosides at fixed concentration on the NADase activity of all three enzymes. To our surprise, we found that two vitamin B3 precursors, NaR and NR [51][52][53], exerted inhibitory effects but with opposing selectivity for hSARM1 vs both hCD38 and Aplysia cyclase (Fig. 5A).…”

Section: Selective Inhibition By Pyridine Ribosidesmentioning

confidence: 86%

Programmed axon death executor SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by physiological levels of NMN, NAD, NADP and other metabolites

Angeletti

Amici

Gilley

et al. 2021

Preprint

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SARM1 is an NAD glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). It has low basal NADase activity that becomes strongly activated by NAD precursor NMN. Very high levels of NAD oppose this activation, competing for the same allosteric site on SARM1′s regulatory ARM domain. Injury or diseases that deplete axons of NMNAT2, an essential enzyme converting NMN to NAD, cause SARM1 activation. The resulting NAD degradation by SARM1, combined with loss of NAD synthesis by NMNAT2, causes rapid depletion of axonal NAD. This NAD loss is widely assumed to mediate axon death and is consequently a key focus for therapeutic strategies for axonopathies. However, like other NAD(P) glycohydrolases, SARM1 has additional enzyme activities whose contributions, consequences and regulation need to be fully understood. Here, we compare the multiple actions and regulation of recombinant human SARM1 with those of two other NAD(P) glycohydrolases, human CD38 and Aplysia californica ADP ribosyl cyclase. We find that SARM1 has the highest transglycosidation (base exchange) activity of these enzymes at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclisation. Moreover, like its NADase and NADPase reactions, SARM1-mediated base exchange at neutral pH is activated by increases in the NMN:NAD ratio, which we show for the first time can act in the presence of physiological levels of both metabolites. We establish that SARM1 base exchange is the most likely physiological source of calcium mobilizing agent NaADP, and potentially of other NAD(P) analogues, which could contribute to axon and cell death. We also identify regulatory effects of free pyridine bases, of NADP and of nicotinic acid riboside (NaR) on SARM1 that represent further therapeutic opportunities. These data will help to pinpoint which of the multiple functions of SARM1 is responsible for axon degeneration and how it can be optimally targeted to block axon degeneration in disease.

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“…To improve the toxicity in yeast, media conditions were manipulated to target pathways in which PNP1 functions. The nicotinamide mononucleotide salvage of NAD + biosynthesis was targeted with forodesine or pnp1Δ in the absence of precursors nicotinic acid and tryptophan (Belenky et al, 2009). Purine salvage (Walther et al, 2010;Tibbetts & Appling, 1997) was targeted with adenosine, natural analogues of adenosine (MTA and dAdo), and different variants of minimal and synthetic 147 media were also assessed but all were unsuccessful in improving the toxicity of forodesine plus deoxyguanosine.…”

Section: Discussionmentioning

confidence: 99%

“…PNP1 is involved in NAD+ biosynthesis, wherein with URH1 and MEU1, constitutes alternative pathways in salvage of nicotinic acid from nicotinamide riboside (via PNP1, URH1, Meu1) and nicotinate riboside (via PNP1, URH1) that is subsequently converted to nicotinamide mononucleotide (Belenky et al, 2007;Belenky et al, 2009). Likewise, tryptophan is also used as a precursor for synthesis of nicotinamide mononucleotide (Bedalov et al, 2003).…”

Section: Nicotinic Acid Depletion Does Not Exacerbate the Growth Defect Of Pnp1δmentioning

confidence: 99%

Elucidating the anti-cancer mechanisms for transition-state structure inhibitors of nucleoside phosphorylases methylthioadenosine-DADMe-immucillin A and forodesine

Coorey¹

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<p>Transition-state structure analogues are among the most powerful chemical inhibitors discovered to date with picomolar efficacy for enzymes. The nucleoside analogue methylthioadenosine-DADMe-immucillin A (MTDIA) is an inhibitor of the enzyme methylthioadenosine phosphorylase (MTAP) in polyamine biosynthesis. The recently approved forodesine (Mundesine®) is an inhibitor of purine nucleoside phosphorylase (PNP) and purine synthesis. Although the targets of these drugs were known at the time of drug design, it is important to know the compendium of cellular perturbations resulting from use of these inhibitors. Several suspected mechanisms of MTDIA and forodesine in progression of apoptotic cell death have been identified but the underlying mechanisms initiating apoptosis remain elusive. We hypothesize that numerous cellular processes are affected in MTDIA and forodesine treatments given the importance of polyamine and purine synthesis in cancer cells. To elucidate the unsuspected mechanisms mediating anti-cancer activity, unbiased genomic analyses were employed using Saccharomyces cerevisiae. First, gene-gene interactions with MEU1 (the MTAP orthologue in yeast) were determined using Synthetic Genetic Array methodology followed by assessment of drug-gene interactions with MTDIA treatment under a MEU1 essential condition with MTA as the sole source of sulphur. Disruptions to suspected mechanisms of amino acid metabolism, carbohydrate metabolism, response to starvation, vesicle-mediated transport, vacuole fusion, lipid homeostasis, chromatin organisation, transcription, and translation were implicated well as unsuspected mechanisms of NAD+ dependent cellular processes, multi-vesicular body formation, endosomal transport, ion homeostasis, mitochondrion organisation, and cell cycle progression. Induction of autophagy was subsequently confirmed with MTDIA to validate the disruptions to vesicle-mediated transport, response to starvation, multi-vesicular body formation and vacuolar fusion. Reduction in ergosterol levels and disruptions to ergosterol biosynthetic proteins were confirmed with MTDIA and meu1Δ to validate disruptions to lipid homeostasis. To complement the genetic analyses, the abundance and localisation of proteins were evaluated in response to MTDIA or MEU1-deficiency. Disruptions to proteins implicated in carbohydrate metabolism, methionine salvage, transcription, translation, transmembrane transport, lipid homeostasis, cell cycle and DNA repair were identified with meu1Δ and MTDIA. Key findings from the analysis of protein abundance and localization were the relocalisation of plasma membrane proteins and disruptions to vesicle mediated transport proteins consistent with the induction of autophagy and disruptions to proteins in homeostasis of all major lipid classes, further corroborating the findings of screening gene deletion mutants for elucidating drug mechanisms. To investigate the mechanisms of forodesine toxicity, genetic interactions with PNP1 (the PNP orthologue in yeast) were determined using Synthetic Genetic Array methodology. Disruptions to amino acid metabolism, starvation responsive genes, vacuolar organisation and vesicle mediated transport, carbohydrate metabolism, lipid homeostasis, chromatin organisation, chromosome segregation, transcription, and translation were identified in response to PNP1-deficency. Despite the introduction of several human genes and supplementation of metabolites required for forodesine bioactivity in humans, forodesine was not sufficiently bioactive in yeast to evaluate sensitivity of gene deletion mutants to forodesine. Overall, chemical genomic analyses in yeast with transition-state structure analogues MTDIA and forodesine effectively highlight the vast number of cellular processes affected by inhibition of a single target. Moreover, genome-wide pre-screening should be carried out in yeast to identify side-effects and secondary effects from drug target inhibition prior to assessing desired and undesired outcomes of highly specific drugs in human cells.</p>

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Nicotinamide riboside and nicotinic acid riboside salvage in fungi and mammals. Quantitative basis for Urh1 and purine nucleoside phosphorylase function in NAD+ metabolism. VOLUME 284 (2009) PAGES 158-164

Cited by 20 publications

References 0 publications

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Nicotinamide Adenine Dinucleotide Metabolism and Neurodegeneration

Programmed axon death executor SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated by physiological levels of NMN, NAD, NADP and other metabolites

Elucidating the anti-cancer mechanisms for transition-state structure inhibitors of nucleoside phosphorylases methylthioadenosine-DADMe-immucillin A and forodesine

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