This topic is lockedVery comprehensive overview of the NAD+ metabolome, modulation of NAD+ metabolism by caloric restriction, enzymes to target, the different precursors and speculation about their therapeutic potential. PDF attached.
Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes
Abstract
Significance: Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+ depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+, and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD+ levels. Recent studies have shown that enhancing NAD+ levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD+anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD+ synthesis pathway in mammalian cells. NAD+ can also be produced by the NAD+ salvage pathway.
Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD+ precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline in degenerative disease states and physiological aging.
Critical Issues: Results obtained in recent years have shown that NAD+ precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD+ synthesis via their location in the NAD+ anabolic pathway. Increased synthesis of NAD+promotes protective cell responses, further demonstrating that NAD+ is a regulatory molecule associated with several biochemical pathways.
Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD+precursors and improved detection methodologies allowing the administration of specific NAD+precursors in the context of patients' NAD+ levels will lead to a better understanding of the therapeutic role of NAD+ precursors in human diseases. Antioxid. Redox Signal. 00, 000–000.
I. Introduction
II. NAD+ Biosynthesis Pathways
A. Tryptophan catabolism via the kynurenine pathway
1. Indoleamine 2,3-dioxygenase-1/2 and tryptophan 2,3-dioxygenase
2. Kynureninase
3. Kynurenine aminotransferases
4. Kynurenine 3-hydroxylase
5. 3-Hydroxyanthranilic acid oxygenase
6. Picolinic acid carboxylase
7. Quinolinic acid phosphoribosyltransferase
8. NAD pyrophosphorylase (NAM mononucleotide adenylyltransferase)
B. NAD+ production from the vitamin niacin 1. NA phosphoribosyltransferase
2. NAM phosphoribosyltransferase
3. NAM N-methyltransferase
4. NR kinases
5. Purine nucleoside phosphorylase 6. Cytosolic 5¢-nucleotidases
III. Biological Roles of NAD+
A. Poly(ADP)-ribosylation and DNA repair
B. CD38/CD39/CD73/CD157 and secondary messenger signaling C. Sirtuin activity
D. Principal causes of NAD+ decline
IV. Redox Roles of Sirtuins and Transcriptional Regulation A. SIRT1
B. SIRT2
C. SIRT3
D. SIRT4
E. SIRT5
F. SIRT6
G. SIRT7
H. Activation by NAD+ precursors
V. Distribution of the NAD+ Metabolome
VI. Subcellular Compartmentalization of NAD+
VII. Modulation of NAD+ Metabolism by Caloric Restriction
VIII. Beneficial Effects of NAD+ Precursors
A. Nicotinic acid
B. Nicotinamide
C. Nicotinamide mononucleotide D. Nicotinamide riboside
E. Nicotinic acid riboside
IX. Pharmacokinetics of NAD+ Precursors A. Nicotinic acid
B. Nicotinamide
C. Nicotinamide mononucleotide
D. Nicotinamide riboside
E. Nicotinic acid riboside
F. Nicotinic acid adenine dinucleotide—a biomarker of elevated NAD+ metabolism
X. Effects of NAD+ Precursors on NAD-Dependent Processes A. NAM and PARPs
B. NAM and sirtuins
C. CD38-mediated processes
D. Redox reactions
XI. Do NAD+ and Related Precursors Display Hormesis?
XII. Limitation of Using In Vitro and In Vivo Studies A. Cell culture systems
B. In vivo models
C. Methods of detection
XIII. Prospects of Using NAD+ Precursors in the Clinic
XIV. Concluding Remarks
Attached Files
Edited by Fredrik, 20 August 2018 - 11:42 AM.
