Nicotinate (niacin) and nicotinamide are precursors of the coenzymes nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+). When NAD+ and NADP+ are interchanged in a reaction with their reduced forms, NADH and NADPH respectively, they are important cofactors in several hundred redox reactions. Nicotinate is synthesized from 2-amino-3-carboxymuconate semialdehyde, an intermediate in the catabolism of the essential amino acid tryptophan (Magni et al. 2004).
View original pathway at Reactome.
Yamamoto-Katayama S, Ariyoshi M, Ishihara K, Hirano T, Jingami H, Morikawa K.; ''Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities.''; PubMedEurope PMCScholia
Ohashi K, Kawai S, Murata K.; ''Identification and characterization of a human mitochondrial NAD kinase.''; PubMedEurope PMCScholia
Zhang X, Kurnasov OV, Karthikeyan S, Grishin NV, Osterman AL, Zhang H.; ''Structural characterization of a human cytosolic NMN/NaMN adenylyltransferase and implication in human NAD biosynthesis.''; PubMedEurope PMCScholia
Hamberg M, Samuelsson B.; ''Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis.''; PubMedEurope PMCScholia
Stockbridge RB, Wolfenden R.; ''The intrinsic reactivity of ATP and the catalytic proficiencies of kinases acting on glucose, N-acetylgalactosamine, and homoserine: a thermodynamic analysis.''; PubMedEurope PMCScholia
Wada M, Yokoyama C, Hatae T, Shimonishi M, Nakamura M, Imai Y, Ullrich V, Tanabe T.; ''Purification and characterization of recombinant human prostacyclin synthase.''; PubMedEurope PMCScholia
Bahn A, Hagos Y, Reuter S, Balen D, Brzica H, Krick W, Burckhardt BC, Sabolic I, Burckhardt G.; ''Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13).''; PubMedEurope PMCScholia
Houten SM, Denis S, Te Brinke H, Jongejan A, van Kampen AH, Bradley EJ, Baas F, Hennekam RC, Millington DS, Young SP, Frazier DM, Gucsavas-Calikoglu M, Wanders RJ.; ''Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia.''; PubMedEurope PMCScholia
Lee HC, Graeff R, Walseth TF.; ''Cyclic ADP-ribose and its metabolic enzymes.''; PubMedEurope PMCScholia
Misumi Y, Ogata S, Ohkubo K, Hirose S, Ikehara Y.; ''Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form.''; PubMedEurope PMCScholia
Ritter M, Buechler C, Boettcher A, Barlage S, Schmitz-Madry A, Orsó E, Bared SM, Schmiedeknecht G, Baehr CH, Fricker G, Schmitz G.; ''Cloning and characterization of a novel apolipoprotein A-I binding protein, AI-BP, secreted by cells of the kidney proximal tubules in response to HDL or ApoA-I.''; PubMedEurope PMCScholia
Sorci L, Cimadamore F, Scotti S, Petrelli R, Cappellacci L, Franchetti P, Orsomando G, Magni G.; ''Initial-rate kinetics of human NMN-adenylyltransferases: substrate and metal ion specificity, inhibition by products and multisubstrate analogues, and isozyme contributions to NAD+ biosynthesis.''; PubMedEurope PMCScholia
Magni G, Amici A, Emanuelli M, Orsomando G, Raffaelli N, Ruggieri S.; ''Enzymology of NAD+ homeostasis in man.''; PubMedEurope PMCScholia
Tempel W, Rabeh WM, Bogan KL, Belenky P, Wojcik M, Seidle HF, Nedyalkova L, Yang T, Sauve AA, Park HW, Brenner C.; ''Nicotinamide riboside kinase structures reveal new pathways to NAD+.''; PubMedEurope PMCScholia
Di Paola S, Micaroni M, Di Tullio G, Buccione R, Di Girolamo M.; ''PARP16/ARTD15 is a novel endoplasmic-reticulum-associated mono-ADP-ribosyltransferase that interacts with, and modifies karyopherin-ß1.''; PubMedEurope PMCScholia
Yan Q, Xu R, Zhu L, Cheng X, Wang Z, Manis J, Shipp MA.; ''BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8.''; PubMedEurope PMCScholia
Beaupre BA, Hoag MR, Roman J, Försterling FH, Moran GR.; ''Metabolic function for human renalase: oxidation of isomeric forms of β-NAD(P)H that are inhibitory to primary metabolism.''; PubMedEurope PMCScholia
Berger F, Lau C, Dahlmann M, Ziegler M.; ''Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms.''; PubMedEurope PMCScholia
Yu M, Schreek S, Cerni C, Schamberger C, Lesniewicz K, Poreba E, Vervoorts J, Walsemann G, Grötzinger J, Kremmer E, Mehraein Y, Mertsching J, Kraft R, Austen M, Lüscher-Firzlaff J, Lüscher B.; ''PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation.''; PubMedEurope PMCScholia
Yalowitz JA, Xiao S, Biju MP, Antony AC, Cummings OW, Deeg MA, Jayaram HN.; ''Characterization of human brain nicotinamide 5'-mononucleotide adenylyltransferase-2 and expression in human pancreas.''; PubMedEurope PMCScholia
Thompson LF, Ruedi JM, Low MG.; ''Purification of 5'-nucleotidase from human placenta after release from plasma membranes by phosphatidylinositol-specific phospholipase C.''; PubMedEurope PMCScholia
Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, Pirinen E, Pulinilkunnil TC, Gong F, Wang YC, Cen Y, Sauve AA, Asara JM, Peroni OD, Monia BP, Bhanot S, Alhonen L, Puigserver P, Kahn BB.; ''Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.''; PubMedEurope PMCScholia
Lee HC.; ''Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization.''; PubMedEurope PMCScholia
Moreschi I, Bruzzone S, Melone L, De Flora A, Zocchi E.; ''NAADP+ synthesis from cADPRP and nicotinic acid by ADP-ribosyl cyclases.''; PubMedEurope PMCScholia
Li J, Mayne R, Wu C.; ''A novel muscle-specific beta 1 integrin binding protein (MIBP) that modulates myogenic differentiation.''; PubMedEurope PMCScholia
Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM.; ''Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization.''; PubMedEurope PMCScholia
Barnett J, Chow J, Ives D, Chiou M, Mackenzie R, Osen E, Nguyen B, Tsing S, Bach C, Freire J.; ''Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system.''; PubMedEurope PMCScholia
Milani M, Ciriello F, Baroni S, Pandini V, Canevari G, Bolognesi M, Aliverti A.; ''FAD-binding site and NADP reactivity in human renalase: a new enzyme involved in blood pressure regulation.''; PubMedEurope PMCScholia
Miyauchi S, Gopal E, Fei YJ, Ganapathy V.; ''Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids.''; PubMedEurope PMCScholia
Bieganowski P, Brenner C.; ''Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.''; PubMedEurope PMCScholia
Lee HC, Munshi C, Graeff R.; ''Structures and activities of cyclic ADP-ribose, NAADP and their metabolic enzymes.''; PubMedEurope PMCScholia
Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL.; ''Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer.''; PubMedEurope PMCScholia
Swinney DC, Mak AY, Barnett J, Ramesha CS.; ''Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid.''; PubMedEurope PMCScholia
Zhou T, Kurnasov O, Tomchick DR, Binns DD, Grishin NV, Marquez VE, Osterman AL, Zhang H.; ''Structure of human nicotinamide/nicotinic acid mononucleotide adenylyltransferase. Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin.''; PubMedEurope PMCScholia
Hara N, Yamada K, Terashima M, Osago H, Shimoyama M, Tsuchiya M.; ''Molecular identification of human glutamine- and ammonia-dependent NAD synthetases. Carbon-nitrogen hydrolase domain confers glutamine dependency.''; PubMedEurope PMCScholia
Hara N, Yamada K, Shibata T, Osago H, Hashimoto T, Tsuchiya M.; ''Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells.''; PubMedEurope PMCScholia
Marbaix AY, Noël G, Detroux AM, Vertommen D, Van Schaftingen E, Linster CL.; ''Extremely conserved ATP- or ADP-dependent enzymatic system for nicotinamide nucleotide repair.''; PubMedEurope PMCScholia
PREISS J, HANDLER P.; ''Biosynthesis of diphosphopyridine nucleotide. II. Enzymatic aspects.''; PubMedEurope PMCScholia
Sasiak K, Saunders PP.; ''Purification and properties of a human nicotinamide ribonucleoside kinase.''; PubMedEurope PMCScholia
Fukuoka SI, Nyaruhucha CM, Shibata K.; ''Characterization and functional expression of the cDNA encoding human brain quinolinate phosphoribosyltransferase.''; PubMedEurope PMCScholia
Nikiforov A, Dölle C, Niere M, Ziegler M.; ''Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation.''; PubMedEurope PMCScholia
Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G.; ''Identification of a novel human nicotinamide mononucleotide adenylyltransferase.''; PubMedEurope PMCScholia
Zimmermann H.; ''5'-Nucleotidase: molecular structure and functional aspects.''; PubMedEurope PMCScholia
Lerner F, Niere M, Ludwig A, Ziegler M.; ''Structural and functional characterization of human NAD kinase.''; PubMedEurope PMCScholia
Samal B, Sun Y, Stearns G, Xie C, Suggs S, McNiece I.; ''Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor.''; PubMedEurope PMCScholia
Schweiger M, Hennig K, Lerner F, Niere M, Hirsch-Kauffmann M, Specht T, Weise C, Oei SL, Ziegler M.; ''Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis.''; PubMedEurope PMCScholia
Niedel J, Dietrich LS.; ''Nicotinate phosphoribosyltransferase of human erythrocytes. Purification and properties.''; PubMedEurope PMCScholia
Chlopicki S, Swies J, Mogielnicki A, Buczko W, Bartus M, Lomnicka M, Adamus J, Gebicki J.; ''1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway.''; PubMedEurope PMCScholia
Abdelraheim SR, Spiller DG, McLennan AG.; ''Mammalian NADH diphosphatases of the Nudix family: cloning and characterization of the human peroxisomal NUDT12 protein.''; PubMedEurope PMCScholia
Garavaglia S, Bruzzone S, Cassani C, Canella L, Allegrone G, Sturla L, Mannino E, Millo E, De Flora A, Rizzi M.; ''The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism.''; PubMedEurope PMCScholia
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Tryptophan is catabolized in seven steps to yield aminomuconate. Intermediates in this process are also used in the synthesis of serotonin and kynurenine (Peters 1991).
Cytosolic nicotinate phosphoribosyltransferase (NaPRT) catalyzes the Mg++-dependent reaction of nicotinate and phosphoribosyl pyrophosphate to form nicotinate mononucleotide (NaMN, nicotinate D-ribonucleotide) and pyrophosphate. The active form of the enzyme is a homodimer (Preiss and Handler 1958; Niedel and Dietrich 1973; Hara et al. 2007).
Cytosolic NAD+ kinase (NADK) catalyses the transfer of a phosphate group from ATP to NAD+, forming NADP+. This is the only way to generate NADP+ in all living organisms. NADK is tetrameric and requires one divalent metal such as Zn2+ per subunit to function correctly (Lerner et al. 2004).
NMNAT2 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Sorci et al. 2007). The active form of the enzyme is a monomer in vitro; Mg2+ is required for activity (Raffaelli et al. 2002; Sorci et al. 2007). Although the predicted amino acid sequence of the enzyme lacks an obvious signal sequence or transmembrane domain (Yalowitz et al. 2004), recombinant FLAG-tagged protein expressed in HeLa cells localizes predominantly to the Golgi apparatus (Berger et al. 2005). Its localization within the Golgi apparatus is unknown and the annotation here is based on the plausible but speculative assumption that the enzyme is associated with the Gogi membrane and accessible from the cytosol. Immunostaining studies indicate that the protein is abundant in Islets of Langerhans and in several regions of the brain (Yalowitz et al. 2004).
Nicotinamide phosphoribosyltransferase (NamPRT) catalyzes the condensation of nicotinamide with 5- phosphoribosyl-1-pyrophosphate to yield nicotinamide D-ribonucleotide (NMN), an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway.
The enzyme, nicotinate nucleotide pyrophosphorylase, is specific for quinolinate. Its activity is strictly dependent on Mg2+ ions being present. A phosphoribosyl group is transferred to quinolinate to form nicotinate D-ribonucleotide. This reaction represents another rate-limiting step of the pathway from tryptophan to NAD+.
NAD synthases 1 and 2 (NADSYN1 and NADSYN2) catalyse the final step in the biosynthesis of NAD+, both in de novo synthesis and in the salvage pathway. The enzymes makes use of an amide donor in the reaction. NADSYNs exist as a homohexamers in the cytosol. The major difference between the two forms is that NADSYN1 appears to be glutamine-dependent whereas NADSYN2 is strictly ammonia-dependent (Hara et al. 2003).
NMNAT3 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Sorci et al. 2007). The active form of the enzyme is a tetramer in vitro (Zhang et al. 2003). Recombinant FLAG-tagged protein expressed in HeLa cells localizes both to the cytosol and to mitochondria (Berger et al. 2005). The cytosolic protein is annotated here.
NMNAT1 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Schweiger et al. 2001). The active form of the enzyme in vitro is a hexamer (Zhou et al. 2002), and its activity is substantially greater in the presence of Zn++ than of Mg++ (Sorci et al. 2007). The predicted amino acid sequence of the enzyme contains a nuclear localization domain and the protein is observed to localize to the nucleus (Schweiger et al. 2001; Berger et al. 2005).
Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994).
The human tumour suppressor gene SLC5A8 encodes sodium-coupled monocarboxylate transporter 1, SMCT1 (also called AIT) and is abundantly expressed in the colon (Coady et al. 2004, Myauchi et al. 2004). When the human protein is expressed in Xenopus oocytes, it was found to transport small monocarboxylates and carboxylate drugs, co-transporting Na+ ions electrogenically (3 Na+ ions co-transported with 1 carboxylate).
Nicotinamide N-methyltransferase (NNMT) is a cytosolic protein which catalyses the N-methylation of nicotinamide (NAM aka vitamin B3) and other pyridines (Aksoy et al. 1994, 1995). It is mainly expressed in the liver and to a lesser extent in the kidney, lung, skeletal muscle, placenta and heart. NAM is a precursor for NAD+, an important cofactor in cellular redox states and energy metabolism. NNMT methylates NAM using S-adenosylmethionine (SAM) as the methyl donor to form 1-methylnicotinamide (MNA). Kraus et al. found Nnmt expression is increased in white adipose tissue and liver of obese and diabetic mice. An Nnmt knockdown stategy could protect against diet-induced obesity by increasing cellular energy expenditure thus could be a target for treating obesity and type 2 diabetes (Kraus et al. 2014). Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007).
NAD(P)H-hydrate epimerase (APOA1BP) is a homodimeric protein located in the mitochondrion (Ritter et al. 2002). Mammalian APOA1BP is able to mediate the epimerisation of the R-form of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration (Marbaix et al. 2011). This is a prerequisite for the S-specific NAD(P)H-hydrate dehydratase to allow the repair of both epimers of NAD(P)HX.
Human ATP-dependent (S)-NAD(P)H-hydrate dehydratase (CARKD) is thought to catalyze the dehydration, and thus repair, of the S-form of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration. The human event is deduced on the basis of evidence from mouse experiments (Marbaix et al. 2011).
The human nudix hydrolase peroxisomal NADH pyrophosphatase (NUDT12) shows in vitro hydrolase activity towards NAD(P)H, NAD(P)+, ADP-ribose and diadenosine triphosphate. Like other NADH diphosphatases of the Nudix family, NUDT12 has a marked substrate preference for reduced nicotinamide nucleotides. It can hydrolyse NAD(H) to the nicotinamide mononucleotide NMN(H) and may act to regulate the concentration of peroxisomal nicotinamide nucleotide cofactors required for oxidative metabolism here (Abdelraheim et al. 2003).
Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007).
Plasma membrane-associated SLC22A13 (solute carrier family 22 member 13, also known as OCTL3 - organic cation transporter-like 3) mediates the uptake of extracellular nicotinate (NCA). The protein is especially abundant in the kidney but is widely expressed in tissues of the body (Bahn et al. 2008).
NMRK1 (nicotinamide riboside kinase 1) catalyzes the reaction of NAR (N-ribosylnicotinate) and ATP to yield NAMN (beta-nicotinate D-ribonucleotide), ADP, and H+ (Tempel et al. 2007). The reaction is annotated with ATP(4-), the major ionized form of ATP at pH 7.2 (Stockbridge & Wolfenden 2009), as the phosphate donor. NMRK1 is a cytosolic enzyme (Nikiforov et al. 2011).
NMRK2 (nicotinamide riboside kinase 2) catalyzes the reaction of NAR (N-ribosylnicotinate) and ATP to yield NAMN (beta-nicotinate D-ribonucleotide), ADP, and H+ (Tempel et al. 2007). The reaction is annotated with ATP(4-), the major ionized form of ATP at pH 7.2 (Stockbridge & Wolfenden 2009), as the phosphate donor. NMRK2 is a cytosolic enzyme (Nikiforov et al. 2011), localized predominantly in myocytes (Li et al. 1999).
NMRK2 (nicotinamide riboside kinase 2) catalyzes the reaction of NR (N-ribosylnicotinamide) and ATP to yield NMN (beta-nicotinamide D-ribonucleotide), ADP, and H+ (Bieganowsky & Brenner 2004; Tempel et al. 2007). The reaction is annotated with ATP(4-), the major ionized form of ATP at pH 7.2 (Stockbridge & Wolfenden 2009), as the phosphate donor. NMRK2 is a cytosolic enzyme (Nikiforov et al. 2011), localized predominantly in myocytes (Li et al. 1999).
NMRK1 (nicotinamide riboside kinase 1) catalyzes the reaction of NR (N-ribosylnicotinamide) and ATP to yield NMN (beta-nicotinamide D-ribonucleotide), ADP, and H+. The enzyme is also active with GTP as a phosphate donor (not annotated here) (Bieganowsky & Brenner 2004; Sasiak & Saunders 1996; Tempel et al. 2007). The reaction is annotated with ATP(4-), the major ionized form of ATP at pH 7.2 (Stockbridge & Wolfenden 2009), as the phosphate donor. NMRK1 is a cytosolic enzyme (Nikiforov et al. 2011).
BST1 dimer associated with the plasma membrane catalyzes the hydrolysis of extracellular NAD+ to yield NAM and ADP-ribose (Yamamoto-Katayama et al. 2002).
Poly (ADP-ribose) polymerases (PARPs) catalyse the poly(ADP-ribosyl)ation posttranslational modification of proteins. At least 18 human members share homology with the catalytic domain of the founding member, PARP1. PARPs cleave the glycosidic bond of NAD+ between nicotinamide (NAM) and ribose followed by the covalent modification of mainly glutamate residues on acceptor proteins with an ADP-ribosyl unit, with subsequent ADP-ribosyl unit additions linked by glycosidic ribose-ribose bonds. NAM can be utilised in the NAD+ regeneration process. Poly(ADP-ribosyl)ation is important in many biological processess including DNA repair, regulation of chromosome structure, transcriptional regulation, mitosis and apoptosis. PARPs can localise to either the cytosol or the nucleus. The cytosolic PARPs described here are PARP9, PARP10 and PARP16 (Yan et al. 2013, Yu et al. 2005, Di Paolo et al. 2012). PARP4, PARP6, PARP8 and PARP14 may also be located in the cytosol with the same functionality.
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (CD38) is a multifunctional enzyme that can catalyse the hydrolysis of NAD+ to form linear ADP-ribose (ADP-D-ribose) and/or cyclization of NAD+ forming cyclic ADP-ribose (cADPR) via a two-step enzymatic reaction. The first common step involves the cleavage of the nicotinamide group of NAD+. The reaction intermediate can either be hydrolysed to form ADP-D-ribose or cyclized to form cADPR (Lee et al. 1995, Moreschi et al. 2006). CD38 can also produce nicotinic acid adenine dinucleotide phosphate (NAADP) (Lee et al. 1999). Both cADPR and NAADP are established second messengers for mobilising intracellular Ca2+ stores (Lee 2012). The reaction annotated here describes the hydrolysis of NAD+ to form ADP-D-ribose.
NMNAT2 catalyzes the reaction of nicotinate D-ribonucleotide and ATP to form deamino-NAD+ (nicotinate adenine dinucleotide) and pyrophosphate (Sorci et al. 2007). The active form of the enzyme is a monomer in vitro; Mg2+ is required for activity (Raffaelli et al. 2002; Sorci et al. 2007). Although the predicted amino acid sequence of the enzyme lacks an obvious signal sequence or transmembrane domain (Yalowitz et al. 2004), recombinant FLAG-tagged protein expressed in HeLa cells localizes predominantly to the Golgi apparatus (Berger et al. 2005). Its localization within the Golgi apparatus is unknown and the annotation here is based on the plausible but speculative assumption that the enzyme is associated with the Gogi membrane and accessible from the cytosol. Immunostaining studies indicate that the protein is abundant in Islets of Langerhans and in several regions of the brain (Yalowitz et al. 2004).
5'-nucleotidase (NT5E, CD73) is able to hydrolyse extracellular nucleotides into membrane permeable nucleosides. It displays a broad specificity, acting on mono- or di-nucleotide nicotinamides and different adenosine phosphates, with maximal activity on 5'-adenosine monophosphate. Human NT5E can hydrolyse both NAD+ and NMN, suggesting a role in NAD metabolism (Garavaglia et al. 2012). NT5E is a glycolipid-anchored plasma membrane enzyme (Misumi et al. 1990) that is active in dimeric form and requires one zinc ion per subunit (Zimmermann 1992).
5'-nucleotidase (NT5E, CD73) is able to hydrolyse extracellular nucleotides into membrane permeable nucleosides. It displays a broad specificity, acting on mono- or di-nucleotide nicotinamides and different adenosine phosphates, with maximal activity on 5'-adenosine monophosphate. Human NT5E can hydrolyse both NAD+ and NMN, suggesting a role in NAD metabolism (Garavaglia et al. 2012). NT5E is a glycolipid-anchored plasma membrane enzyme (Misumi et al. 1990) that is active in dimeric form and requires one zinc ion per subunit (Zimmermann 1992).
NAD kinase is the sole NADP(+) biosynthetic enzyme. A cytosolic form of NAD kinase is already characterised but recently, a mitochondrial form has been found to exist. Mitochondrial NAD kinase 2 (NADK2 aka C5orf33, MNADK, NADKD1) uses ATP to phosphorylate NAD+ to NADP+ (Ohashi et al. 2012). NADK2 is ubiquitously expressed and is more abundant than its cytosolic counterpart. Defects in NADK2 can cause 2,4-dienoyl-CoA reductase deficiency (DECRD), a rare, autosomal recessive, inborn error of polyunsaturated fatty acids and lysine metabolism, resulting in mitochondrial dysfunction (Houten et al. 2014).
Renalase (RNLS) is a flavoprotein that is secreted by the kidney and circulates in blood from where it can regulate blood pressure, regulate sodium and phosphate excretion and display cardioprotectivity through a mechanism which is not understood to date. RNLS, using FAD as cofactor, can oxidise isomeric forms of beta-NAD(P)H that can arise either by nonspecific reduction of beta-NAD(P)+ or by tautomerisation of beta-NAD(P)H (Milani et al. 2011, Beaupre et al. 2015). These forms are 1,2- and 1,6-dihydroNAD(P) (dh-beta-NAD(P)) and are potent inhibitors of primary metabolism dehydrogenases. RNLS may thus play a role in eliminating these isomeric forms which threaten normal respiratory activity.
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