NAD(P) Biosynthesis Enzymes as Potential Targets for Selective Drug Design

Abstract

NAD(P) biosynthetic pathways can be considered a generous source of enzymatic targets for drug development. Key reactions for NAD(P) biosynthesis in all organisms, common to both de novo and salvage routes, are catalyzed by NMN/NaMN adenylyltransferase (NMNAT), NAD synthetase (NADS), and NAD kinase (NADK). These reactions represent a three-step pathway, present in the vast majority of living organisms, which is responsible for the generation of both NAD and NADP cellular pools. The validation of these enzymes as drug targets is based on their essentiality and conservation among a large variety of pathogenic microorganisms, as well as on their differential structural features or their differential metabolic contribution to NAD(P) homeostasis between microbial and human cell types. This review describes the structural and functional properties of eubacterial and human enzymes endowed with NMNAT, NADS, and NADK activities, as well as with nicotinamide phosphoribosyltransferase (NamPRT) and nicotinamide riboside kinase (NRK) activities, highlighting the species-related differences, with emphasis on their relevance for drug design. In addition, since the overall NMNAT activity in humans is accounted by multiple isozymes differentially involved in the metabolic activation of antineoplastic compounds, their individual diagnostic value for early therapy optimization is outlined. The involvement of human NMNAT in neurodegenerative disorders and its role in neuroprotection is also discussed.

Increased plasma nicotinamide phosphoribosyltransferase is associated with a hyperproliferative phenotype and restrains disease progression in MPN‐associated myelofibrosis

“…Unique among malignancies, high levels of eNAMPT in MPN-associated myelofibrosis predicted a restraint of the disease progression toward a more severe disease phenotype and leukemia. As a key regulator of NAD1 biosynthesis, NAMPT is deemed to be a potential cancer therapeutic target [47][48][49][50]. In MPN-associated myelofibrosis a full exploitation of the relevance of anti-NAMPT therapy needs a full understanding of the complex relation between inflammation, NAMPT, myeloproliferation, and disease progression.…”

Phytoplasma Genomes: Evolution Through Mutually Complementary Mechanisms, Gene Loss and Horizontal Acquisition

“…Transferring electrons from one metabolite to another, the coenzyme participates in numerous metabolic redox reactions (Belenky et al 2007;Pollak et al 2007). Additionally, some NAD + is converted into the coenzyme nicotinamide adenine dinucleotide phosphate (NADP NAD synthetase, catalyzing a two-step reaction that transforms deamido-NAD into NAD, is an essential enzyme involved in both the de novo biosynthesis and salvage of NAD + (Bi et al 2011;Magni et al 2009). Phytoplasma genomes lack a gene encoding a canonical NH 3 / glutamine-dependent NAD synthetase such as is present in all known bacteria with walls and in cell wall-less bacteria including mycoplasmas and spiroplasmas.…”

Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells

“…NMN and NAMN can also be generated from the nucleosides NR and NAR via their phosphorylation by nicotinamide riboside kinases (Fig. 1A) (2,8,10,11).…”