Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans

Wang, Wenqing; McReynolds, Melanie R.; Goncalves, Jimmy; Shu, Muya; Dhondt, Ineke; Braeckman, Bart P.; Lange, Stephanie E.; Kho, Kelvin; Detwiler, Ariana C.; Pacella, Marisa J.; Hanna-Rose, Wendy

doi:10.1074/jbc.m115.662916

Cited by 24 publications

(28 citation statements)

References 46 publications

(70 reference statements)

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“…A, supplementation of QA to pnc-1(pk9605) mutants restores the gonad developmental delay but has no effect on umps-1(ok2703);pnc-1(pk9605) animals, whereas supplementation of NA restores gonad development in both genetic backgrounds. Note that the penetrance of the gonad development phenotype is influenced by food type (15,18). The penetrance is lower (more normal animals) in this experiment than that reported in Fig.…”

Section: Umps-1 Contributes To Nad ؉ Biosynthesiscontrasting

confidence: 58%

“…We previously reported that salvage NAD ϩ synthesis is critical for the normal progression of gonad development, for full fecundity, and for efficient glucose metabolism in the cytosol (12,15,17,18). Interestingly, loss of NAD ϩ de novo synthesis also resulted in decreased progeny production compared with wild type.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that reduced levels of NAD ϩ caused by the lack of salvage synthesis in pnc-1 mutants impair reproductive development in C. elegans (15). Although the levels of nicotinic acid (NA), the product of PNC-1, are reduced almost 20-fold in the mutant, NAD ϩ levels are only reduced by about 30% (15). Therefore, we hypothesized that alternative NAD ϩ biosynthetic pathways could respond to the loss of salvage synthesis to maintain global NAD ϩ levels.…”

Section: Supplementation With De Novo Precursors Reverses Nad ؉Dependmentioning

confidence: 99%

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Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid

McReynolds

Wang²,

Holleran

et al. 2017

Journal of Biological Chemistry

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NAD biosynthesis is an attractive and promising therapeutic target for influencing health span and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD biosynthetic pathways. Here, we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, are reported to lack a NAD biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of NAD biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact biosynthesis pathway for NAD from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD levels and partially reversed NAD-dependent phenotypes caused by mutation of , which encodes a nicotinamidase required for NAD salvage biosynthesis, demonstrating contribution of synthesis to NAD homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosphoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD biosynthesis creates novel possibilities for manipulating NAD biosynthetic pathways, which is key for the future of therapeutics.

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Section: Umps-1 Contributes To Nad ؉ Biosynthesiscontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Supplementation With De Novo Precursors Reverses Nad ؉Dependmentioning

confidence: 99%

See 1 more Smart Citation

Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid

McReynolds

Wang²,

Holleran

et al. 2017

Journal of Biological Chemistry

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“…Given conservation of NAM-receptor interactions across these phyla, we expect Brugia OSM-9 orthologs to also respond to NAM. However, the pharmacology and subunit interactions of Brugia OSM-9 may differ (e.g., filarial parasites do not have a homolog of ocr-4 ( Figure 3A)), and NAM is an endogenous metabolite in C. elegans that has pleiotropic effects (54,(56)(57)(58)(59)(60) . This compelled us to use a genetic approach to more directly test whether Brugia OSM-9 and TAX-4 are involved in parasite chemotaxis behavior.…”

Section: Bp-osm-9 and Bp-tax-4 Rnai Inhibits Chemoattraction Of Infecmentioning

confidence: 99%

Genetic and functional diversification of chemosensory pathway receptors in mosquito-borne filarial nematodes

Wheeler

Heimark

Airs

et al. 2019

Preprint

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Lymphatic filariasis (LF) afflicts over 60 million people worldwide and leads to severe pathological outcomes in chronic cases. The filarial nematode parasites that cause LF require both arthropod (mosquito) intermediate hosts and mammalian definitive hosts for their propagation. The invasion and migration of filarial parasites through host tissues are complex and critical to survival, yet little is known about the receptors and signaling pathways that mediate taxis in these medically important species.To better understand filarial chemosensation we employ comparative genomics, transcriptomics, reverse genetics, and chemical approaches to identify putative chemosensory receptor proteins and perturb chemosensory phenotypes in filarial nematode parasites. We find that chemoreceptor family size is correlated with the presence of environmental (extra-host) stages in nematode life cycles, and that filarial parasites contain a compact and highly-diverged chemoreceptor complement and lineage-specific ion channels that are predicted to operate downstream of chemoreceptor activation. In Brugia malayi, an etiological agent of LF, chemoreceptor expression patterns correspond to distinct parasite migration events across the life cycle. To interrogate the role of chemosensation in host migration, arthropod infectious stage (microfilariae) and vertebrate infectious stage (L3) Brugia parasites were incubated in nicotinamide, an agonist of the nematode transient receptor potential (TRP) channel osm-9 . Exposure of microfilariae to nicotinamide alters intra-mosquito migration while exposure of L3s reduces chemotaxis towards host-associated cues in vitro . Nicotinamide exposure also modulates thermosensory responses in L3s, suggesting a polymodal sensory role for Brugia osm-9 . Reverse genetic studies implicate both osm-9 and the cyclic nucleotide-gated (CNG) channel subunit tax-4 in larval chemotaxis towards host serum, while these ion channel subunits do not rescue chemosensory defects in C. elegans osm-9 and tax-4 knock-out strains. Together, these data reveal genetic and functional diversification of chemosensory signaling proteins in filarial nematode parasites, and encourage a more thorough investigation of clade and parasite-specific facets of nematode sensory receptor biology.

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“…In human cancer cells and C. elegans the depletion of NAD levels during NAMPT inhibition is associated with decreased glycolytic flux through attenuation of GAPDH activity . This effect impairs both the generation of ATP and cycling of NAD(H).…”

Section: Resultsmentioning

confidence: 99%

Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores

Kropp

Broniowska

Waas

et al. 2017

Stem Cells Translational Medicine

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To address concerns regarding the tumorigenic potential of undifferentiated human pluripotent stem cells (hPSC) that may remain after in vitro differentiation and ultimately limit the broad use of hPSC‐derivatives for therapeutics, we recently described a method to selectively eliminate tumorigenic hPSC from their progeny by inhibiting nicotinamide phosphoribosyltransferase (NAMPT). Limited exposure to NAMPT inhibitors selectively removes hPSC from hPSC‐derived cardiomyocytes (hPSC‐CM) and spares a wide range of differentiated cell types; yet, it remains unclear when and how cells acquire resistance to NAMPT inhibition during differentiation. In this study, we examined the effects of NAMPT inhibition among multiple time points of cardiomyocyte differentiation. Overall, these studies show that in vitro cardiomyogenic commitment and continued culturing provides resistance to NAMPT inhibition and cell survival is associated with the ability to maintain cellular ATP pools despite depletion of NAD levels. Unlike cells at earlier stages of differentiation, day 28 hPSC‐CM can survive longer periods of NAMPT inhibition and maintain ATP generation by glycolysis and/or mitochondrial respiration. This is distinct from terminally differentiated fibroblasts, which maintain mitochondrial respiration during NAMPT inhibition. Overall, these results provide new mechanistic insight into how regulation of cellular NAD and energy pools change with hPSC‐CM differentiation and further inform how NAMPT inhibition strategies could be implemented within the context of cardiomyocyte differentiation. Stem Cells Translational Medicine 2017;6:1191–1201

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Comparative Metabolomic Profiling Reveals That Dysregulated Glycolysis Stemming from Lack of Salvage NAD+ Biosynthesis Impairs Reproductive Development in Caenorhabditis elegans

Abstract: Background: Loss of NADϩ salvage biosynthesis causes a reproductive delay in C. elegans.

Cited by 24 publications

References 46 publications

Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid

Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid

Genetic and functional diversification of chemosensory pathway receptors in mosquito-borne filarial nematodes

Cardiomyocyte Differentiation Promotes Cell Survival During Nicotinamide Phosphoribosyltransferase Inhibition Through Increased Maintenance of Cellular Energy Stores

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