Abstract
Nicotinamide adenine dinucleotide (NAD) serves as an essential redox co-factor and mediator of multiple biological processes. Besides its well-established role in electron transfer reactions, NAD serves as a substrate for other biotransformations, which, at the molecular level, can be classified as protein post-translational modifications (protein deacylation, mono-, and polyADP-ribosylation) and formation of signaling molecules (e.g., cyclic ADP ribose). These biochemical reactions control many crucial biological processes, such as cellular signaling and recognition, DNA repair and epigenetic modifications, stress response, immune response, aging and senescence, and many others. However, the links between the biological effects and underlying molecular processes are often poorly understood. Moreover, NAD has recently been found to tag the 5′-ends of some cellular RNAs, but the function of these NAD-capped RNAs remains largely unrevealed. Synthetic NAD analogs are invaluable molecular tools to detect, monitor, structurally investigate, and modulate activity of NAD-related enzymes and biological processes in order to aid their deeper understanding. Here, we review the recent advances in the design and development of NAD analogs as probes for various cellular NAD-related enzymes, enzymatic inhibitors with anticancer or antimicrobial therapeutic potential, and other NAD-related chemical biology tools. We focus on research papers published within the last 10 years.
Highlights
Nicotinamide adenine dinucleotide (NAD) is one of the most important and ubiquitous cofactors present both in prokaryotic and eukaryotic organisms
NAD can be phosphorylated by NAD kinases to NADP, which is another redox cofactor utilized in biosynthetic pathways and protection against oxidants [1]
We reviewed the recent progress in the design of NAD analogs as molecular probes and
Summary
NAD is one of the most important and ubiquitous cofactors present both in prokaryotic and eukaryotic organisms. The essential role of NAD is the participation in cellular redox processes maintained by NAD+ /NADH interconversion (Figure 1A). NAD can be phosphorylated by NAD kinases to NADP, which is another redox cofactor utilized in biosynthetic pathways and protection against oxidants [1]. In addition to the role in enzyme-catalyzed electron-transfer reactions, NAD is utilized by various enzymes to modify cellular biopolymers or produce signaling molecules (Figure 1B) [2,3,4]. PARP inhibitors have potential as anticancer and chemo-sensitizing drugs [5,6]. Another class of disease-associated NAD-dependent enzymes are sirtuins, which utilize
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