scholarly journals NAD+ Metabolism and Diseases with Motor Dysfunction

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1776
Author(s):  
Samuel Lundt ◽  
Shinghua Ding
Keyword(s):  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Mammalian Cells ◽  
De Novo ◽  
Motor Dysfunction ◽  
Salvage Pathway ◽  
Motor Neuron Diseases ◽  
Nad Metabolism ◽  
Charcot Marie Tooth Disease ◽  
Salvage Pathways

Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot–Marie–Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson’s disease and Huntington’s disease. Nicotinamide adenine dinucleotide (NAD+) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. NAD+ can be reversibly oxidized-reduced or directly consumed by NAD+-dependent proteins. NAD+ is synthesized in cells via three different paths: the de novo, Preiss–Handler, or NAD+ salvage pathways, with the salvage pathway being the primary producer of NAD+ in mammalian cells. NAD+ metabolism is being investigated for a role in the development of neurodegenerative diseases. In this review, we discuss cellular NAD+ homeostasis, looking at NAD+ biosynthesis and consumption, with a focus on the NAD+ salvage pathway. Then, we examine the research, including human clinical trials, focused on the involvement of NAD+ in MNDs and other neurodegenerative diseases with motor dysfunction.

scholarly journals Renal hypertrophy in experimental diabetes. The activity of the ‘de novo’ and salvage pathways of purine [corrected] synthesis

1988 ◽  
Vol 249 (3) ◽  
pp. 911-914 ◽  
Author(s):  
S Kunjara ◽  
S J Beardsley ◽  
A L Greenbaum
Keyword(s):  
Nucleic Acids ◽  
De Novo ◽  
Experimental Diabetes ◽  
Salvage Pathway ◽  
Phosphoribosyl Pyrophosphate ◽  
Renal Hypertrophy ◽  
Early Diabetes ◽  
Nucleotide Synthesis ◽  
Main Route ◽  
Salvage Pathways

Measurements were made of the activity of phosphoribosyl pyrophosphate amidotransferase (PPRibP-At, EC 2.4.2.14) and of adenine (APRT, EC 2.4.2.7) and hypoxanthine (HPRT, EC 2.4.2.8) phosphoribosyltransferases, representing the ‘de novo’ and salvage pathways respectively. PPRibP-At activity increased within 3 days of diabetes, whereas APRT and HPRT increased later. Incorporation of [14C]formate and of [8-14C]adenine into the nucleic acids of kidney slices showed that formate was incorporated earlier, and to a greater extent, than was adenine. These results indicate that, although the ‘de novo’ pathway for nucleotide synthesis is the main route in early diabetes, the salvage pathway assumes greater importance at later stages.

scholarly journals Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration

2020 ◽  
Vol 31 (20) ◽  
pp. 2158-2163 ◽  
Author(s):  
Amy Northrop ◽  
Holly A. Byers ◽  
Senthil K. Radhakrishnan
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Membrane Protein ◽  
Neurodegenerative Diseases ◽  
Mammalian Cells ◽  
Therapeutic Strategy ◽  
De Novo ◽  
Degradation Pathway ◽  
Special Focus ◽  
Homeostatic Mechanism

The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.

scholarly journals DRES-09. REGULATORY EFFECTS OF THE CILIARY GTPASE ARL13B ON PURINE METABOLISM IN GBM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi73-vi73
Author(s):  
Miranda Saathoff ◽  
Jack Shireman ◽  
Eunus Ali ◽  
Cheol Park ◽  
Issam Ben-Sahra ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Specific Activity ◽  
Purine Metabolism ◽  
P Value ◽  
Salvage Pathway ◽  
De Novo Synthesis ◽  
Dna Double Strand Breaks ◽  
Purine Nucleotides ◽  
Regulatory Effects

Abstract Glioblastoma (GBM) is the most common form of adult primary brain cancer. Despite an aggressive treatment regimen – surgical resection, irradiation, and temozolomide (TMZ) chemotherapy – patients’ prognosis is still grim. TMZ acts by methylating purines, specifically at the O6 and N7 positions of guanine, to induce cytotoxic DNA double-strand breaks. We thus wanted to explore how purine metabolism may contribute to TMZ-resistance. In mammalian cells, purine nucleotides can be recycled by the salvage pathway or generated via de novo synthesis. The salvage pathway is energetically inexpensive relative to de novo thus, highly proliferative GBM cells preferentially utilize the salvage pathway. We have shown that salvage synthesis is reduced in response to TMZ (p-value=0.0021), hinting that the cells may utilize de novo to evade therapy induced alkylation of purines. Using immunoprecipitation-mass spectroscopy analysis, we found a novel interaction between the ciliary GTPase ARL13B and IMPDH2, the rate-limiting enzyme in de novo synthesis. We have shown that this interaction, occurring at the C-terminal domain of ARL13B, plays a significant role in the regulation of purine biosynthesis as abolishing it through ARL13B knockdown reduced flux through de novo (p-value< 0.0001) synthesis as measured by the specific activity of IMPDH2. Further, the lentiviral-mediated rescue of ARL13B brings IMPDH2 activity back to basal levels (p< 0.0001). Given its canonical function as a GTPase, we hypothesize that ARL13B acts as a novel regulator of de novo synthesis by sequestering GDP, allowing IMPDH2 to sense and respond to the cytosolic levels of guanine nucleotides. Without ARL13B the de novo pathway is halted, forcing the cells to rely on salvage to replenish nucleotide pools. Reliance on this pathway in the presence of TMZ causes cells to incorporate damaged nucleotides as a result of the drug’s alkylating action leading to the increased therapeutic efficacy of TMZ.

scholarly journals NAD+ Metabolism, Metabolic Stress, and Infection

2021 ◽  
Vol 8 ◽  
Author(s):  
Benjamin Groth ◽  
Padmaja Venkatakrishnan ◽  
Su-Ju Lin
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Budding Yeast ◽  
Metabolic Stress ◽  
Growth Conditions ◽  
Kynurenine Pathway ◽  
Nad Metabolism ◽  
Human Disorders ◽  
Stress Signals ◽  
Salvage Pathways

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

scholarly journals Enzymes of the pathway of purine synthesis in the rat mammary gland. Changes in the lactation cycle and the effects of diabetes

1988 ◽  
Vol 250 (2) ◽  
pp. 395-399 ◽  
Author(s):  
S Beardsley ◽  
S Kunjara ◽  
A L Greenbaum
Keyword(s):  
Mammary Gland ◽  
De Novo ◽  
Salvage Pathway ◽  
Adenine Phosphoribosyltransferase ◽  
Phosphoribosyl Pyrophosphate ◽  
Purine Synthesis ◽  
Enzyme Change ◽  
Rat Mammary Gland ◽  
Salvage Pathways ◽  
Lactation Cycle

Measurements were made of the activities of the enzymes of the ‘de novo’ and salvage pathways of purine synthesis [phosphoribosyl pyrophosphate amidotransferase (EC 2.4.2.14), adenine phosphoribosyltransferase (EC 2.4.2.7) and hypoxanthine phosphoribosyltranferase (EC 2.4.2.8)] at different stages of the lactation cycle, and the effects of diabetes on the activity of these enzymes in lactation were studied. A distinctive pattern of enzyme change was observed, in which the ‘de novo’ pathway enzyme phosphoribosyl pyrophosphate amidotransferase increased sharply between days 10 and 14 of pregnancy, and then remained sensibly constant until the height of lactation, whereas the enzymes of the salvage pathway increased later in pregnancy and continued to rise during lactation. Diabetes severely depressed the activity of the enzymes of the salvage pathway, but appeared to be without effect on the ‘de novo’ pathway enzyme. These results are discussed in relation to the provision of purine precursors from tissues outside the mammary gland.

scholarly journals Purine-Metabolising Enzymes and Apoptosis in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1354 ◽  
Author(s):  
Camici ◽  
Garcia-Gil ◽  
Pesi ◽  
Allegrini ◽  
Tozzi
Keyword(s):  
Molecular Mechanisms ◽  
Purine Nucleoside Phosphorylase ◽  
De Novo ◽  
Tumour Cells ◽  
Purine Nucleotide ◽  
Salvage Pathway ◽  
Nucleotide Synthesis ◽  
Deoxynucleoside Triphosphate ◽  
Hypoxanthine Guanine Phosphoribosyltransferase ◽  
Salvage Pathways

The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

scholarly journals Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway

2018 ◽  
Author(s):  
Igor Shats ◽  
Juan Liu ◽  
Jason G. Williams ◽  
Leesa J. Deterding ◽  
Chaemin Lim ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mammalian Cells ◽  
Resistance Mechanism ◽  
Mammalian Host ◽  
Salvage Pathway ◽  
Drug Induced ◽  
Nad Metabolism ◽  
Nad Synthesis

AbstractNicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in diverse cellular processes including metabolism, DNA repair, and aging1. NAD metabolism is critical to maintain cellular homeostasis in response to the environment, and disruption of this homeostasis is associated with decreased cellular NAD levels in aging2. Conversely, elevated NAD synthesis is required to sustain the increased metabolic rate of cancer cells3,4. Consequently, therapeutic strategies aimed to both upregulate NAD (i.e. NAD-boosting nutriceuticals) or downregulate NAD (inhibitors of key NAD synthesis enzymes) are being actively investigated5–10. However, how this essential metabolic pathway is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer cancer cells with the resistance to inhibitors of NAMPT, the rate limiting enzyme in the main vertebrate NAD salvage pathway. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a key precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. This bacteria-enabled resistance mechanism that allows the mammalian host to bypass the drug-induced metabolic block represents a novel paradigm in drug resistance. This host-microbe metabolic interaction also enables bacteria to dramatically enhance the NAD-boosting efficiency of nicotinamide supplementationin vitroandin vivo, demonstrating a crucial role of microbes, gut microbiota in particular, in organismal NAD metabolism.

scholarly journals Regulation of the salvage pathway of deoxynucleotides synthesis in apoptosis induced by growth factor deprivation

1996 ◽  
Vol 316 (2) ◽  
pp. 421-425 ◽  
Author(s):  
F. Javier OLIVER ◽  
Mary K. L. COLLINS ◽  
Abelardo LÓPEZ-RIVAS
Keyword(s):  
Dna Fragmentation ◽  
Kinase Inhibitors ◽  
Phorbol Esters ◽  
De Novo ◽  
Salvage Pathway ◽  
Dntp Pool ◽  
Kinase C ◽  
Growth Factor Deprivation ◽  
Salvage Pathways ◽  
Haemopoietic Cells

Here we describe changes in dNTP metabolism that precede DNA fragmentation in a model of apoptosis driven by deprivation of the cytokine interleukin 3 (IL-3). In haemopoietic BAF3 cells, IL-3 withdrawal leads to a rapid decrease in the size of dATP, dTTP and dGTP pools without affecting dCTP levels. This imbalance in dNTP pools precedes DNA fragmentation and is accompanied by down-regulation of enzymes controlling the de novo and salvage pathways of dNTP synthesis, ribonucleotide reductase and thymidine kinase (TK) respectively. Readdition of IL-3 results in a rapid, protein synthesis-independent restoration of normal dNTP pools, enhanced TK activity and increased precursor incorporation through the salvage pathway. Up-regulation of TK activity after IL-3 readdition is prevented by the protein kinase C (PKC) inhibitor staurosporin, but not by tyrosine kinase inhibitors. Furthermore activation of PKC by phorbol esters mimics the stimulatory effect of IL-3 on TK activity, suggesting that PKC might be involved in regulating this effect. These results indicate that regulation by IL-3 of the salvage pathway of dNTP synthesis plays a role in the maintenance of cellular dNTP pool balance and suggests that alterations in dNTP metabolism after IL-3 deprivation could be a relevant event in the commitment of haemopoietic cells to apoptosis.

Nuclear Folate Metabolism

2018 ◽  
Vol 38 (1) ◽  
pp. 219-243 ◽  
Author(s):  
Martha S. Field ◽  
Elena Kamynina ◽  
James Chon ◽  
Patrick J. Stover
Keyword(s):  
Mammalian Cells ◽  
Genome Stability ◽  
De Novo ◽  
Genome Instability ◽  
Childbearing Age ◽  
Definitive Evidence ◽  
Dna Replication And Repair ◽  
One Carbon Metabolism ◽  
Salvage Pathways ◽  
Thymidylate Synthesis

Despite unequivocal evidence that folate deficiency increases risk for human pathologies, and that folic acid intake among women of childbearing age markedly decreases risk for birth defects, definitive evidence for a causal biochemical pathway linking folate to disease and birth defect etiology remains elusive. The de novo and salvage pathways for thymidylate synthesis translocate to the nucleus of mammalian cells during S- and G2/M-phases of the cell cycle and associate with the DNA replication and repair machinery, which limits uracil misincorporation into DNA and genome instability. There is increasing evidence that impairments in nuclear de novo thymidylate synthesis occur in many pathologies resulting from impairments in one-carbon metabolism. Understanding the roles and regulation of nuclear de novo thymidylate synthesis and its relationship to genome stability will increase our understanding of the fundamental mechanisms underlying folate- and vitamin B12–associated pathologies.

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

Sign in / Sign up

Export Citation Format

Share Document