Abstract
Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.
Highlights
Nicotinamide adenine dinucleotide (NAD+ ) is an essential pyridine nucleotide cofactor that is crucial for the activity of numerous enzymes involved in fundamental cellular processes, such as cellular energy metabolism and adaptive response to stress conditions.Being NAD+, a limiting factor for the activity of dehydrogenase and NAD+ -utilizing enzymes, such as (ADP-ribosyl) transferases (ART), Sirtuins (Sirt) and NAD+ -dependent histone deacetylases, the availability of NAD+ and an optimal NAD+/NADH ratio govern vital cellular redox and enzymatic reactions, including mitochondrial biology, energy production, metabolism, DNA repair, epigenetic modulation of gene expression, apoptosis and intracellular signaling [1]
Using FK866 to inhibit nicotinamide phosphoribosyltransferase (NAMPT), A375 cells were treated with nicotinamide, nicotinic acid, nicotinamide riboside, kynurenine and quinolinic acid as precursors of NAD+, showing that each substrate has organelle-specific ability to rescue from NAMPT block [38]
It can be expected that supplementation of NAD+ precursors may delay the onset and progression of ADP-ribosylation-linked disease states, as it has been done for metabolic and degenerative diseases with decreased NAD+ levels
Summary
Nicotinamide adenine dinucleotide (NAD+ ) is an essential pyridine nucleotide cofactor that is crucial for the activity of numerous enzymes involved in fundamental cellular processes, such as cellular energy metabolism and adaptive response to stress conditions. We will discuss mammalian enzymes responsible for for protein MARylation, and their pathophysiological functions by focusing on the protein MARylation, and their pathophysiological functions by focusing on the potential of potential of inhibiting their enzymatic activities in order to provide novel therapeutic inhibiting their enzymatic activities in order to provide novel therapeutic perspectives in perspectives in chronic human diseases. In this regard, the impact of NAD+ homeostasis.
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