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NAD metabolism


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NAD metabolism

NAD metabolism.

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

Tryptophan is the de novo precursor of NAD + in all vertebrates andalmost 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 Kynurenine3-monooxygenase ( KMO ) [12], [13], [14], [15] to form 3-Hydroxy-(L)-kynurenine. Kynureninase ( Kynu ) thenforms 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 andrearrangement to form Quinolate, which is converted to Nicotinic acidmononucleotide ( NaMN ) by Nicotinate-nucleotide pyrophosphorylase [carboxylating]( NADC ) [24], [25]. 

NaMN then can transform in two ways, the first way with forming NicotinateD-ribonucleoside by the action of the following enzymes: Cytosolic 5'-nucleotidase 1B( 5'-NT1B ), Cytosolic purine 5'-nucleotidase ( 5'-NTC ), Cytosolic5'-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 ofNicotinamide ribonucleoside from Nicotinamid-mononucleotide ( NMN ). Thisreaction can proceeds in the opposite direction, but it catalyzed by already otherenzymes: Nicotinamide riboside kinase 2 ( MIBP ) and by Nicotinamide ribosidekinase 1 ( NRK1 ) [27]. And the second way of transformationNaMN is forming Deamido-NAD (' +) by the action offollowing 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 + fromNMN.

Purine nucleoside phosphorylase ( PNPH ) is an enzyme which catalyze thereaction formation Nicotinate from NMN [34], [35] andthe 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 2precursor ( BST1 ) [39], [40] and by ADP-ribosyl cyclase 1( CD38 ). These enzymes also catalyze the five other reactions: 1- formation2'-Phospho-cADPribose and Nicotinamide from NAD(P) ('+)[41], [42], [43] for CD38 (References on theliterature remain the same for all reactions if others are not showed ), 2 - furtherconversation 2'-Phospho-cADPribose into the 2'-Phospho-ADPribose,3-formation cADPribose and Nicotinamid e from NAD ('+)[44] for CD38, 4 - furher transformation cADPribose into theADP-D-ribose [45], [46], [43], [47],[48], [49] for CD38. ADP-D-ribose and2'-phospho-ADPribose participate in ATP metabolism. And the last reaction isformation NAD ('+) from Deamido-NAD ('+) andNicotinamide. One more way NAD ('+) formation fromDeamido-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 alsocatalyze formation NAD ('+) from NAD(P) ('+) andformation cADPribose from 2'-Phospho-cADPribose.

As we can see, Nicotinamide meets on a metabolic card a twice that speaks aboutimportance of this compound in transformation NAD +.Nicotinamide can undergo transformation into the Nicotinamide N-oxide bythe action of Cytochrome P450 2D6 ( CYP2D6 ) [58], [59] and then by theaction of Aldehyde oxidase ( AOX1 ) into theN('1)-Methyl-2-pyridone-5-carboxamide [60], [61], [61], [62], [63] or into theN('1)-Methyl-4-pyridone-3-carboxamide [64], [65].Formation Nicotinamide from NAD + also catalyzed byNAD-dependent deacetylase sirtuin-1 ( Sirtuin1 ) [66], [67], [68], NAD-dependent deacetylase sirtuin-2 ( Sirtuin2 )[69], [70], [71], NAD-dependent deacetylasesirtuin-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 calledpentosyltransferases: 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 reactioncatalyzed by different enzymes: Ectonucleotide pyrophosphatase/phosphodiesterase familymember 1 ( ENPP1 ) [99], [100], [101], [102], Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor (ENPP2 ) [103], [104], [105], Ectonucleotidepyrophosphatase/phosphodiesterase family member 3 ( ENPP3 ) [106], andby another enzyme -Peroxisomal NADH pyrophosphatase NUDT12 ( NUD12 ) [107]. These all enzymes also catalyze reaction formation NaMN fromDeamido-NAD ('+).

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