Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors
Abstract:A large number of enzymes that use nicotinamide adenine dinucleotide NAD or its phosphorylated form NADP as a cofactor or substrate were found to play an important role in the growth and reproduction of living organisms. NAD(P)-dependent and NAD(P)- utilizing enzymes [NAD(P)-addicted?] have been extensively investigated and implicated in a wide variety of diseases. NAD, generally considered a key component involved in redox reactions, has been found to participate in a broad spectrum of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. The reduced form of NADP, i.e. NADPH, guards the cell against oxidative stress and it has been suggested that suppression of NADPH oxidase activity could result in anti-angiogenesis and anticancer effects. Consequently, small molecule NAD(P)-based inhibitors that selectively bind at the NAD(P)-binding domain of the targeted enzyme have been designed for novel treatment of medical disorders. The NAD(P)-binding domain is modular in nature; it can be divided into three sub-sites, the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Each sub-site plays an important role in securing proper and tight binding; however, each has its own requirements. In this review we discuss a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to these sub-sites, as well as to the whole binding domain. We have focused on potential selectivity of NAD(P)-like molecules toward targeted enzymes and their potential application in biology and medicine.
Document Type: Research Article
Publication date: 2011-05-01
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