NAD metabolism

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) [28], [30], [31], [32], [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 Nicotinamide from NAD^('+) [44] for CD38, 4 - furher transformation cADPribose into the ADP-D-ribose [43], [45], [46], [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], [54], [55], [56], 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 [58], [61], [62], [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], NAD-dependent deacetylase sirtuin-2 (Sirtuin2) [68], [69], [70], NAD-dependent deacetylase sirtuin-3, mitochondrial precursor (Sirtuin3) [71], [72], NAD-dependent deacetylase sirtuin-4 (Sirtuin4) [73], [74], NAD-dependent deacetylase sirtuin-5 (Sirtuin5) [73], NAD-dependent deacetylase sirtuin-7 (Sirtuin7) [75], [76], [77]. 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) [78], Ecto-ADP-ribosyltransferase 3 precursor (NAR3) [79], [80], Ecto-ADP-ribosyltransferase 4 precursor (NAR4) [80], [81], Ecto-ADP-ribosyltransferase 5 precursor (NAR5) [82], [83], [84], [85], Mono-ADP-ribosyltransferase sirtuin-6 (Sirtuin6) [75], [77], [86], Poly [ADP-ribose] polymerase 1 (PARP-1) [87], [88], Poly [ADP-ribose] polymerase 2 (PARP-2) [89], [90], [91], Poly [ADP-ribose] polymerase 3 (PARP-3) [89], Poly [ADP-ribose] polymerase 4 (VPARP) [92], [93], Tankyrase-1 [94], [95], [96], Tankyrase 2 [96], [97].

NAD^('+) can hydrolyze with forming NMN. This reaction catalyzed by different enzymes: Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) [98], [99], [100], [101], Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor (ENPP2) [102], [103], [104], Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3) [105], and by another enzyme -Peroxisomal NADH pyrophosphatase NUDT12 (NUD12) [106]. 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) [107]. In the second case NAD⁺ react with NADPH with forming NADP+ and NADH is catalyzed by NAD(P) transhydrogenase, mitochondrial precursor (NNTM) [108], [109]. Then NADH can transform into the NAD⁺ in the presence of NADH-cytochrome b5 reductase 3 (CYB5R3) [110], [111], [112], [113].

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