Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery

@article{Khan2007NicotinamideAD,
  title={Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery},
  author={Javed A. Khan and Farhad Forouhar and Xiao Tao and Liang Tong},
  journal={Expert Opinion on Therapeutic Targets},
  year={2007},
  volume={11},
  pages={695 - 705}
}
Nicotinamide adenine dinucleotide (NAD+) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD+ metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington’s disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD+ biosynthesis, is… 
View on Taylor & Francis
tonglab.biology.columbia.edu
145 Citations
Highly Influential Citations
6
Background Citations
55
Methods Citations
3
Results Citations
2

145 Citations

Therapeutic potential of nicotinamide adenine dinucleotide (NAD).
The NAD+ metabolism of Leishmania, notably the enzyme nicotinamidase involved in NAD+ salvage, offers prospects for development of anti‐parasite chemotherapy
TLDR
It is demonstrated that Leishmania species can only rely on the salvage of NAD+ building blocks, and the crystal structure of the parasite protein has been solved, showing prospects for design of inhibitors to be used as leads for development of new drugs.
Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, in Human Cancer Cells
TLDR
The effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on glycolysis, the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle, and serine biosynthesis in cancer cells and tumor xenografts are examined.
Metabolomics Analysis of Metabolic Effects of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibition on Human Cancer Cells
TLDR
The effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells are investigated to suggest that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.
Nicotinamide adenine dinucleotide and its related precursors for the treatment of Alzheimer's disease
TLDR
NAD+ and its precursors may represent an important therapeutic strategy to maintain optimal cellular homoeostatic functions in the brain.
NMNAT expression and its relation to NAD metabolism.
TLDR
Steps involved in NAD synthesis are being utilized as targets for chemoprevention, radiosensitization and therapy of wide range of diseases, such as cancer, multiple sclerosis, neurodegeneration and Huntington's disease.
NMN/NaMN adenylyltransferase (NMNAT) and NAD kinase (NADK) inhibitors: chemistry and potential therapeutic applications.
TLDR
A comprehensive summary of NMNAT and NADK inhibitors highlighting their chemical modifications by different synthetic approaches, and structure-activity relationships depending on their potential therapeutic applications is provided.
A fluorometric assay for high-throughput screening targeting nicotinamide phosphoribosyltransferase.
Probing the Druggability Limits for Enzymes of the NAD Biosynthetic Network in Glioma
TLDR
Reconstruction of a biochemical network of NAD biosynthesis consisting of 22 proteins, 36 metabolites, and 86 parameters, tuned to mimic the conditions in glioma is reported, which defines a maximal extent of inhibition possible for a chosen enzyme in the context of its network.
Nicotinamide phosphoribosyltransferase (Nampt) in carcinogenesis: new clinical opportunities
TLDR
Nampt not only maintains the balance of cellular metabolism, but also has a profound influence on multiple aspects of carcinogenesis, and elucidation of these mechanisms opens the door for future clinical applications targeting this protein.
...
...

References

SHOWING 1-10 OF 140 REFERENCES
The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals
TLDR
It is proposed that the presumed multiple effects of Nampt/PBEF/visfatin may be entirely explained by its role as an intra and extracellular NAD biosynthetic enzyme, which provides an important insight into developing preventive/therapeutic interventions for metabolic complications, such as obesity and diabetes.
FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis.
TLDR
This work has identified the first low molecular weight compound, designated FK866, which induces apoptosis by highly specific, noncompetitive inhibition of nicotinamide phosphoribosyltransferase (NAPRT), a key enzyme in the regulation of NAD+ biosynthesis from the natural precursor Nicotinamide.
Structure and function of nicotinamide mononucleotide adenylyltransferase.
TLDR
This overview describes the most recent findings on NMNATs from bacteria, archaea, yeast, animal and human sources, with detailed consideration of their major kinetic, molecular and structural features.
Crystal structure of quinolinic acid phosphoribosyltransferase from Mmycobacterium tuberculosis: a potential TB drug target.
Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents
TLDR
The structures suggest that Asp219 is a determinant of substrate specificity of NMPRTase, which is confirmed by the authors' mutagenesis studies, and show that FK866 should compete directly with the nicotinamide substrate.
Inosine 5'-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases.
  • A. Ratcliffe
  • Biology, Medicine
    Current opinion in drug discovery & development
  • 2006
TLDR
This review will highlight recent advances in the IMPDH field, with a focus on the discovery and development of non-nucleoside IM PDH inhibitors.
Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans
Metabolism of the novel IMP dehydrogenase inhibitor benzamide riboside.
TLDR
H hepatic metabolism may be an important factor also for BR activation and inactivation and should be considered in human liver during cancer therapy when BR is used as a single drug or in combination with other anticancer agents.
Cell Life versus cell longevity: the mysteries surrounding the NAD+ precursor nicotinamide.
TLDR
The development of nicotinamide is described as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span.
Enzymology of NAD+ synthesis.
TLDR
This review describes the enzymes involved in pyridine nucleotide metabolism, starting with a detailed consideration of the anaerobic and aerobic pathways leading to quinolinate, a key precursor of NAD+.
...
...