Pathway Map Details

NAD metabolism

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Sirtuin3,,, Sirtuin6, Sirtuin2, NRK1, AOX1, Sirtuin4, CD38, IAP,,, Nicotinamide, PARP-1,,,, Sirtuin5, Sirtuin7, PLAP-like, ALPL, TDO2,,, 2.7.1.-,, Tankyrase 2,, NADPH,,,, KMO, PARP-3, PPNK, arylformamidase, VPARP, NNTM, ENPP1, KYNU, Nicotinamide, ENPP3, NADH, NAR5, NT5C3,, ENPP2, NAR3,, N1-Methyl-2-pyridone-5-carboxamide, NAD synthetase 1, N-Methyl nicotinamide,, NMNA3, 3HAO, NaMN, 2'-Phospho- ADP ribose,, NAR1, NAR4, Nicotinamide N-oxide, NAD('+), N('1)-Methyl-4- pyridone-3- carboxamide, NADC, NT5M, ADP-(D)-ribose, cADP-ribose, NT5C,, 2'-Phospho- cADPribose,,,, spontaneous,, PARP-2, NMNA2,,, NADP('+), Nicotinamide ribonucleoside, NMNA1, 2-Amino-3-carboxy muconate semialdehyde,, 3-Hydroxy- (L)- kynurenine, ALPP,,, 3-Hydroxy- anthranilate, Deamido-NAD(P)('+), Deamido-NAD('+), L-Kynurenine, MIBP, N-Formyl- (L)-kynurenine, NUD12,, L-Tryptophan,, 3.5.1.-, Nicotinate D-ribonucleoside,, INDO, NNMT, Quinolinate, CYB5R3, BST1,,, PBEF, 5'-NTC, 5'-NT1B,, CYP2D6, Nicotinate, 5'-NT1A,, PNPH, NMN, 5'-NTD, Sirtuin1, Tankyrase 1


NAD metabolism.

Nicotinamide adenine dinucleotide ( NAD + ) and its phosphorylated and reduced forms, NADP +, NADH and NADPH, have central roles in cellular metabolism and energy production as hydride-accepting and hydride-donating coenzymes.

Tryptophan is the de novo precursor of NAD + in all vertebrates and almost all eukaryotes investigated. De novo synthesis begins with the conversion of (L)-Tryptophan to N'-Formyl-(L)-kynurenine by either Tryptophan 2, 3-dioxygenase ( TDO2 ) [1], [2] or Indoleamine 2, 3-dioxygenase ( INDO ) [2], [3], [4], [5], [6], [7]. Probable arylformamidase ( Arylformamidase ) then forms (L)-Kynurenine [8], [9], [10], [11], which is used as substrate by Kynurenine 3-monooxygenase ( KMO ) [12], [13], [14], [15] to form 3-Hydroxy-(L)-kynurenine. Kynureninase ( Kynu ) then forms 3-Hydroxy-anthranilate [16], [17], [18], which is converted to 2-Amino-3-carboxymuconate semialdehyde by 3-Hydroxyanthranilate 3, 4-dioxygenase ( 3HAO ) [19], [20], [21], [22], [23]. The semialdehyde undergoes a spontaneous condensation and rearrangement to form Quinolate, which is converted to Nicotinic acid mononucleotide ( NaMN ) by Nicotinate-nucleotide pyrophosphorylase [carboxylating] ( NADC ) [24], [25].

NaMN then can transform in two ways, the first way with forming Nicotinate D-ribonucleoside by the action of the following enzymes: Cytosolic 5'-nucleotidase 1B ( 5'-NT1B ), Cytosolic purine 5'-nucleotidase ( 5'-NTC ), Cytosolic 5'-nucleotidase 3 ( NT5C3 ), 5'(3')-Deoxyribonucleotidase, cytosolic type (NT5C ), 5'(3')-Deoxyribonucleotidase, mitochondrial precursor ( NT5M ), Cytosolic 5'-nucleotidase 1A ( 5'-NT1A ), 5'-nucleotidase precursor ( 5'-NTD ) [26]. These enzymes also catalyze the reaction formation of Nicotinamide ribonucleoside from Nicotinamid-mononucleotide ( NMN ). This reaction can proceeds in the opposite direction, but it catalyzed by already other enzymes: Nicotinamide riboside kinase 2 ( MIBP ) and by Nicotinamide riboside kinase 1 ( NRK1 ) [27]. And the second way of transformation NaMN is forming Deamido-NAD (' +) by the action of following enzymes: Nicotinamide mononucleotide adenylyltransferase 3 ( NMNA3 ) [28], Nicotinamide mononucleotide adenylyltransferase 2 ( NMNA2 ) [29], Nicotinamide mononucleotide adenylyltransferase 1 ( NMNA1 ) [30], [31], [32], [28], [33]. These enzymes also participate in reaction formation of NAD + from NMN.

Purine nucleoside phosphorylase ( PNPH ) is an enzyme which catalyze the reaction formation Nicotinate from NMN [34], [35] and the reaction formation Nicotinamide from Nicotinamide ribonucleoside [36], [37], [38].

Nikotinate transforms into the Nicotinamide and Deamido-NAD(P) ('+) by the action of the following enzymes: ADP-ribosyl cyclase 2 precursor ( BST1 ) [39], [40] and by ADP-ribosyl cyclase 1 ( CD38 ). These enzymes also catalyze the five other reactions: 1- formation 2'-Phospho-cADPribose and Nicotinamide from NAD(P) ('+) [41], [42], [43] for CD38 (References on the literature remain the same for all reactions if others are not showed ), 2 - further conversation 2'-Phospho-cADPribose into the 2'-Phospho-ADPribose, 3-formation cADPribose and Nicotinamid e from NAD ('+) [44] for CD38, 4 - furher transformation cADPribose into the ADP-D-ribose [45], [46], [43], [47], [48], [49] for CD38. ADP-D-ribose and 2'-phospho-ADPribose participate in ATP metabolism. And the last reaction is formation NAD ('+) from Deamido-NAD ('+) and Nicotinamide. One more way NAD ('+) formation from Deamido-NAD ('+) exists by the action of Glutamine-dependent NAD (+) synthetase ( NAD synthetase 1 ) [50], [51], [52].

Deamido-NAD ('+) is obtained from Deamido-NAD(P) ('+) by the action of group of alkaline phosphatase: Alkaline phosphatase, placental type precursor ( ALPP ) [53], [54], [55], Intestinal alkaline phosphatase precursor ( IAP ) [53], [56], [54], [55], Alkaline phosphatase, tissue-nonspecific isozyme precursor ( ALPL ) [53], [54], [55], [57], Alkaline phosphatase, placental-like precursor ( PLAP-like ) [53], [54], [55]. These enzymes also catalyze formation NAD ('+) from NAD(P) ('+) and formation cADPribose from 2'-Phospho-cADPribose.

As we can see, Nicotinamide meets on a metabolic card a twice that speaks about importance of this compound in transformation NAD +. Nicotinamide can undergo transformation into the Nicotinamide N-oxide by the action of Cytochrome P450 2D6 ( CYP2D6 ) [58] and by consecutive reaction at first into the N-Methylnicotinamide in the presence of Nicotinamide N-methyltransferase ( NNMT ) [59], [60] and then by the action of Aldehyde oxidase ( AOX1 ) into the N('1)-Methyl-2-pyridone-5-carboxamide [61], [62], [62], [58], [63] or into the N('1)-Methyl-4-pyridone-3-carboxamide [64], [65]. Formation Nicotinamide from NAD + also catalyzed by NAD-dependent deacetylase sirtuin-1 ( Sirtuin1 ) [66], [67], [68], NAD-dependent deacetylase sirtuin-2 ( Sirtuin2 ) [69], [70], [71], NAD-dependent deacetylase sirtuin-3, mitochondrial precursor ( Sirtuin3 ) [72], [73], NAD-dependent deacetylase sirtuin-4 ( Sirtuin4 ) [74], [75], NAD-dependent deacetylase sirtuin-5 ( Sirtuin5 ) [74], NAD-dependent deacetylase sirtuin-7 ( Sirtuin7 ) [76], [77], [78]. Formation Nicotinamide from NAD + also proceeds in the presence of class of enzymes called pentosyltransferases: GPI-linked NAD(P)(+)--arginine ADP-ribosyltransferase 1 precursor ( NAR1 ) [79], Ecto-ADP-ribosyltransferase 3 precursor ( NAR3 ) [80], [81], Ecto-ADP-ribosyltransferase 4 precursor ( NAR4 ) [81], [82], Ecto-ADP-ribosyltransferase 5 precursor ( NAR5 ) [83], [84], [85], [86], Mono-ADP-ribosyltransferase sirtuin-6 ( Sirtuin6 ) [76], [87], [78], Poly [ADP-ribose] polymerase 1 ( PARP-1 ) [88], [89], Poly [ADP-ribose] polymerase 2 ( PARP-2 ) [90], [91], [92], Poly [ADP-ribose] polymerase 3 ( PARP-3 ) [90], Poly [ADP-ribose] polymerase 4 ( VPARP ) [93], [94], Tankyrase-1 [95], [96], [97], Tankyrase 2 [98], [97].

NAD ('+) can hydrolyze with forming NMN. This reaction catalyzed by different enzymes: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 ( ENPP1 ) [99], [100], [101], [102], Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor ( ENPP2 ) [103], [104], [105], Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 ( ENPP3 ) [106], and by another enzyme -Peroxisomal NADH pyrophosphatase NUDT12 ( NUD12 ) [107]. These all enzymes also catalyze reaction formation NaMN from Deamido-NAD ('+).

NADP + can obtain from from NAD + by two ways. In the first case reaction catalyzed by NAD kinase ( PPNK ) [108]. In the second case NAD + react with NADPH with forming NADP+ and NADH is catalyzed by NAD(P) transhydrogenase, mitochondrial precursor ( NNTM ) [109], [110]. Then NADH can transform into the NAD + in the presence of NADH-cytochrome b5 reductase 3 ( CYB5R3 ) [111], [112], [113], [114].


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