NAD+ Metabolism, Metabolic Stress, and Infection

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

Functional Prediction of Biological Profile During Eutrophication in Marine Environment

“…These BPs and MPs involve biochemical reactions and pathways that ultimately lead to the formation of precursor metabolites and substances from which energy is derived. 39 - 44 This energy production is essential for the regulation of nutrient content during stress, to persist long enough, continue its cycle, and invade a new host. 45 …”

Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease

“…Intracellular 5-HT regulates cell redox potential during its monoamine oxidase-initiated metabolism to 5-hydroxyindole acetate. Breakdown of serotonin through this pathway results in NADH/NADPH production, key molecules in both combatting virus-killing oxidative assaults and production of metabolic products and energy reserve required for efficient viral replication ( Boccuto et al, 2013 ; Yano et al, 2015 ; Fiore and Murray, 2021 ; Groth et al, 2021 ). In agreement with this idea, we observed a significant ~16-fold increase in expression of MAOB in the RT 2 Profiler Array, suggesting that metabolic products downstream of serotonin may provide an intracellular environment conducive for efficient viral replication.…”

Selective targeting of CD38 hydrolase and cyclase activity as an approach to immunostimulation

“…Decreases in NAD + levels are associated with various metabolic diseases (diabetes, obesity, dyslipidemia and nonalcoholic fatty liver) 48,49 and in aging. 50–52 It also plays a major role in the immune response to infectious disease 53 including COVID-19. 54 ADO is a potent immunosuppressant, and plays a similar role in the development and progression of disease.…”