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Measuring NAD+ and Related Metabolites Using Liquid Chromatography Mass Spectrometry life Review NADomics: Measuring NAD+ and Related Metabolites Using Liquid Chromatography Mass Spectrometry Nady Braidy 1,2,* , Maria D. Villalva 1 and Ross Grant 3,4 1 Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia; [email protected] 2 Euroa Centre, UNSW School of Psychiatry, NPI, Prince of Wales Hospital, Barker Street, Randwick, Sydney, NSW 2031, Australia 3 School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; [email protected] 4 Australasian Research Institute, Sydney Adventist Hospital, Sydney, NSW 2076, Australia * Correspondence: [email protected]; Tel.: +61-2-9382-3763; Fax: +61-2-9382-3774 Abstract: Nicotinamide adenine dinucleotide (NAD+) and its metabolome (NADome) play impor- tant roles in preserving cellular homeostasis. Altered levels of the NADome may represent a likely indicator of poor metabolic function. Accurate measurement of the NADome is crucial for biochemi- cal research and developing interventions for ageing and neurodegenerative diseases. In this mini review, traditional methods used to quantify various metabolites in the NADome are discussed. Owing to the auto-oxidation properties of most pyridine nucleotides and their differential chemical stability in various biological matrices, accurate assessment of the concentrations of the NADome is an analytical challenge. Recent liquid chromatography mass spectrometry (LC-MS) techniques which overcome some of these technical challenges for quantitative assessment of the NADome in the blood, CSF, and urine are described. Specialised HPLC-UV, NMR, capillary zone electrophoresis, Citation: Braidy, N.; Villalva, M.D.; or colorimetric enzymatic assays are inexpensive and readily available in most laboratories but lack Grant, R. NADomics: Measuring the required specificity and sensitivity for quantification of human biological samples. LC-MS repre- NAD+ and Related Metabolites Using Liquid Chromatography Mass sents an alternative means of quantifying the concentrations of the NADome in clinically relevant Spectrometry. Life 2021, 11, 512. biological specimens after careful consideration of analyte extraction procedures, selection of internal https://doi.org/10.3390/life11060512 standards, analyte stability, and LC assays. LC-MS represents a rapid, robust, simple, and reliable assay for the measurement of the NADome between control and test samples, and for identifying Academic Editors: Chiara Villa and biological correlations between the NADome and various biochemical processes and testing the Jong-Hyuk Yoon efficacy of strategies aimed at raising NAD+ levels during physiological ageing and disease states. Received: 11 April 2021 Keywords: NAD+; nicotinamide; ageing; plasma; biomarker Accepted: 24 May 2021 Published: 31 May 2021 Publisher’s Note: MDPI stays neutral 1. Introducing NADomics as a Tool for Quantification of the NADome in with regard to jurisdictional claims in Biological Samples published maps and institutional affil- NADomics is the high-throughput study of nicotinamide adenine dinucleotide (NAD+) iations. and its related metabolites. NAD+ is an essential coenzyme that is present in all or- ganisms [1]. NAD+ serves as a major coenzyme for enzymatic reduction–oxidation re- actions and ATP production. More recently, NAD+ has also been shown to be a cru- cial co-substrate for numerous enzymes (i.e., sirtuins, NAD+ glycohydrolase (CD38), Copyright: © 2021 by the authors. poly(adenosine diphosphate–ribose) polymerases (PARPs)) [2–4]. The term NADomics Licensee MDPI, Basel, Switzerland. is an analogy to metabolomics, the study of the metabolome. The word NADome is a This article is an open access article portmanteau of NAD+ and its related metabolome. The NADome is the entire set of distributed under the terms and NAD+ metabolites that are anabolised or catabolised by an organism or system (Figure1 ). conditions of the Creative Commons The emerging field of NADomics has enabled the identification and quantification of Attribution (CC BY) license (https:// ever-increasing numbers of NAD-related metabolites. creativecommons.org/licenses/by/ 4.0/). Life 2021, 11, 512. https://doi.org/10.3390/life11060512 https://www.mdpi.com/journal/life Life 2021, 11, 512 2 of 11 Life 2021, 11, 512 2 of 11 of NADomics has enabled the identification and quantification of ever-increasing num- bers of NAD-related metabolites. Figure 1.1. NADNAD+ metabolism in eukaryotic cells. NAD + anabolismanabolism from from tryptophan tryptophan occurs occurs by by the de novo kynureninekynurenine pathway (KP).(KP). NADNAD++ precursors via the salvage pathway include nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), (NR), and and nicotinic nicotinic acid acid riboside riboside (NAR). (NAR). The The enz enzymeyme nicotinamide nicotinamide phosphoribosyltransferase phosphoribosyltransferase (NAMPT) (NAMPT) converts con- vertsNAM NAM to nicotinamide to nicotinamide mononucl mononucleotideeotide (NMN). (NMN). Nicotinamide Nicotinamide mononucleotide mononucleotide adenylyltransferase adenylyltransferase (NMNAT1-3) (NMNAT1-3) converts + convertsNMN to NMNNAD . toNAM NAD can+. NAMbe methylated can be methylated to N-methyl-nicotinamide to N-methyl-nicotinamide (MeNAM) (MeNAM)by the action by of the nicotinamide action of nicotinamide N-methyl- transferase (NNMT). NADH represents the reduced form of NAD+. NADP+ is the phosphorylated form of NAD+. NADP+ N-methyltransferase (NNMT). NADH represents the reduced form of NAD+. NADP+ is the phosphorylated form of NAD+. can be reduced to NADPH by NAD kinases (NADK1,2). PARPs, Sirtuins, and CD38 NAD+ glycohydrolases are known as NADP+ can be reduced to NADPH by NAD kinases (NADK1,2). PARPs, Sirtuins, and CD38 NAD+ glycohydrolases NAD+ consumers, leading to the generation of NAM. Nicotinic acid phosphoribosyltransferase (NAPRT) converts NA to + arenicotinic known acid as mononucleo NAD consumers,tide (NAMN), leading which to the is generation then converted of NAM. to NAD Nicotinic+ by NMNAT1-3. acid phosphoribosyltransferase NAR needs to be converted (NAPRT) to + convertsNAMN to NA yield to nicotinicNAD+ synthesis acid mononucleotide via nicotinamide (NAMN), riboside which kinases is then (NRK1,2). converted NRK1,2 to NAD also convertby NMNAT1-3. NR to NMN. NAR NAR needs can to beform converted NA via purine to NAMN nucleoside to yield phosphorylase NAD+ synthesis (PNP). via nicotinamide PNP are also riboside capable kinases of converting (NRK1,2). NR NRK1,2to NAM. also convert NR to NMN. NAR can form NA via purine nucleoside phosphorylase (PNP). PNP are also capable of converting NR to NAM. NAD+ and its reduced form NADH can be phosphorylated to NADP+ and NADPH, + + whichNAD serveand as major its reduced coenzymes form in NADH over 400 can oxidoreductase be phosphorylated enzymes to NADP [5]. NADand+ NADPH,serves as + whicha hydrogen serve acceptor as major allowing coenzymes the in transfer over 400 of oxidoreductaseelectrons for oxidation–reduction enzymes [5]. NAD (i.e.,serves redox) as reactionsa hydrogen leading acceptor to allowingATP production the transfer in ofthe electrons mitochondria for oxidation–reduction [1]. NAD+ glycohydrolases (i.e., redox) + (CD38,reactions CD157) leading are to involved ATP production in the production in the mitochondria of calcium-mobilising [1]. NAD messengers,glycohydrolases ADP- (CD38,ribose (ADPR) CD157) and are involvedits cyclic inform the (cADPR) production [6]. of PARP-mediated calcium-mobilising ADP-ribosylation messengers, ADP- uses ribose (ADPR) and its cyclic form (cADPR) [6]. PARP-mediated ADP-ribosylation uses the the ADPR moiety of NAD+ to repair DNA, leading to the breakdown NAD+ to nicotina- ADPR moiety of NAD+ to repair DNA, leading to the breakdown NAD+ to nicotinamide mide (NAM) and an ADP-ribosyl product [7]. Sirtuins are a family of class III NAD+-de- (NAM) and an ADP-ribosyl product [7]. Sirtuins are a family of class III NAD+-dependent pendent histone deacetylases that exhibit protein lysine deacetylase, and partial ADPR histone deacetylases that exhibit protein lysine deacetylase, and partial ADPR transferase transferase activities [8]. Deacetylation occurs when the modified lysine side chain is cou- activities [8]. Deacetylation occurs when the modified lysine side chain is coupled to the pled to the cleavage of the glycosidic bonds in NAD+, leading to the generation of the cleavage of the glycosidic bonds in NAD+, leading to the generation of the deacetylated deacetylated lysine, acetylated ADPR, and NAM as by-products [9]. These processes are lysine, acetylated ADPR, and NAM as by-products [9]. These processes are dependent on dependent on NAD+ availability, and NAM is an endogenous inhibitor of CD38, PARP, NAD+ availability, and NAM is an endogenous inhibitor of CD38, PARP, and sirtuins [5]. and sirtuins [5]. Continuous replenishment of cellular NAD+ levels is important for normal cellular Continuous replenishment of cellular NAD+ levels is important for normal cellular survival [10]. The de novo NAD+ biosynthesis pathway in most cells is dependent on survival [10]. The de novo NAD+ biosynthesis pathway in most cells is dependent on the the amino acid tryptophan via the kynurenine pathway. When the availability of dietary amino acid tryptophan via the kynurenine pathway. When the availability of dietary tryp- tryptophan is limited, the efficiency of the conversion of tryptophan to NAD+ decreases + tophanbelow theis limited, well-established the efficiency conversion
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