NAD + Metabolism, Metabolic Stress, and Infection
Journal: 2021/June - Frontiers in Molecular Biosciences
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.
Keywords: budding yeast; de novo NAD+ synthesis; immune response; infection; kynurenine metabolites; quinolinic acid; siutuin.
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NAD<sup>+</sup> Metabolism, Metabolic Stress, and Infection

Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, United States,
Edited by:Nady Braidy, University of New South Wales, Australia
Reviewed by:Gayathri Sundaram, St Vincent’s Hospital Sydney, Australia

Mara Fiorani, University of Urbino Carlo Bo, Italy

*Correspondence: Su-Ju Lin, ude.sivadcu@nils
This article was submitted to Protein Chemistry and Enzymology, a section of the journal Frontiers in Molecular Biosciences
Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California, Davis, Davis, CA, United States,
Edited by:Nady Braidy, University of New South Wales, AustraliaReviewed by:Gayathri Sundaram, St Vincent’s Hospital Sydney, Australia

Mara Fiorani, University of Urbino Carlo Bo, Italy

This article was submitted to Protein Chemistry and Enzymology, a section of the journal Frontiers in Molecular Biosciences
Received 2021 Mar 26; Accepted 2021 May 5.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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.

Keywords: de novo NAD synthesis, kynurenine metabolites, quinolinic acid, budding yeast, siutuin, immune response, infection
Abstract
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