Abstract
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 presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD(+) metabolic enzymes, with emphasis on their relevance for drug discovery.
Publication types
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Research Support, N.I.H., Extramural
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Review
MeSH terms
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Acrylamides / pharmacology
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Acrylamides / therapeutic use
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Adenosine Diphosphate Ribose / metabolism
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Aging / metabolism
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / metabolism
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Clinical Trials, Phase II as Topic
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Cyclic ADP-Ribose / physiology
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DNA Damage
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Drug Design*
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Enzyme Inhibitors / pharmacology
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Humans
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Kynurenine / metabolism
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Mice
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NAD / metabolism*
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NAD / physiology
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neurodegenerative Diseases / drug therapy
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Neurodegenerative Diseases / metabolism
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Poly Adenosine Diphosphate Ribose / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Sirtuins / antagonists & inhibitors
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Sirtuins / metabolism
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Tryptophan / metabolism
Substances
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Acrylamides
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Antineoplastic Agents
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Enzyme Inhibitors
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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Neuroprotective Agents
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Piperidines
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NAD
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Cyclic ADP-Ribose
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Adenosine Diphosphate Ribose
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Poly Adenosine Diphosphate Ribose
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Kynurenine
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Tryptophan
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Sirtuins