Current Pharmaceutical Design - Volume 15, Issue 1, 2009

Nicotinamide adenine dinucleotide (NAD) research has progressed from the initial vitamin discovery phase in 1937 with the cure for the NAD deficiency disease pellagra [1], to discoveries in the 1950s of activities observed after application at pharmacological doses. These latter applications include benefits to mental health [2, 3] and lipodystrophy [4], where nicotinic acid remains the most effective means of elev Read More

Dietary niacin deficiency, and pharmacological excesses of nicotinic acid or nicotinamide, have dramatic effects on cellular NAD pools, ADP-ribose metabolism, tissue function and health. ADP-ribose metabolism is providing new targets for pharmacological intervention, and it is important to consider how the supply of vitamin B3 may directly influence ADP-ribosylation reactions, or create interactions with other drugs designe Read More

A rapidly growing body of information has suggested that NAD (including NAD+ and NADH) and NADP (including NADP+ and NADPH) could be new fundamental factors in cell death: Many studies have indicated key roles of poly (ADP-ribose) polymerases and sirtuins --- two families of NAD-dependent enzymes --- in cell death; and NAD may also affect cell survival by influencing mitochondrial permeability transition, apoptosi Read More

New interest in NAD biology has recently been revived, and enzymes involved in NAD biosynthetic pathways have been identified and characterized in mammals. Among them, nicotinamide phosphoribosyltransferase (Nampt) has drawn much attention in several different fields, including NAD biology, metabolism, and immunomodulatory response. The research history of this protein is peculiar and controversial, and its physiol Read More

The maintenance and regulation of cellular NAD(P)(H) content and its influence on cell function involves many metabolic pathways, some of which remain poorly understood. Niacin deficiency in humans, which leads to low NAD status, causes sun sensitivity in skin, indicative of deficiencies in responding to UV damage. Animal models of niacin deficiency demonstrate genomic instability and increased cancer development in se Read More

The intersection between regulatory pathways responsive to metabolic fluctuation on one hand, and to cellular stress on the other, is a fascinating area within which NAD/NADH responsive proteins play a major role [1, 2]. A key player amongst these is SIRT1, a member of the mammalian sirtuin family (SIRT1-7). SIRT1 is an NAD-dependent deacetylase with critical functions in the maintenance of homeostasis and cell survival. In t Read More

The sirtuins are protein modifying enzymes widely distributed in all forms of life. The sirtuins are principally NAD+-dependent protein acetyl-lysine deacetylases that reverse acetyl-modifications of proteins. The sirtuins are implicated in a variety of adaptations to reduced nutritional intake, and increase lifespan in several model organisms, such as yeast, flies and worms. The human sirtuins (SIRT1-7) have been identified to regul Read More

CD38 is a multifunctional enzyme that uses nicotinamide adenine dinucleotide (NAD) as a substrate to generate second messengers. Recently, CD38 was also identified as one of the main cellular NADases in mammalian tissues and appears to regulate cellular levels of NAD in multiple tissues and cells. Due to the emerging role of NAD as a key molecule in multiple signaling pathways, and metabolic conditions it is imper Read More

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and ly Read More

Schizophrenia is a common, debilitating mental illness that has persisted over the generations. For a disease with a strong genetic component, such prevalence has been difficult to understand in evolutionary terms. A model for its prevalence as a phenotype is presented in this manuscript, based on reports of specific differences in gene expression, metabolite levels and historical epidemiology. The selective force that underlies th Read More

Cardiovascular disease (CVD) is the most prevalent disease worldwide and there is intense interest in pharmaceutical approaches to reduce the burden of this chronic, aging-related condition. The sirtuin (SIRT) family of NAD+- dependent protein deacetylases and ADP-ribosyltransferases have emerged as exciting targets for CVD management that can impact the cardiovascular system both directly and indirectly, the latte Read More