Nicotinamide adenine dinucleotide biosynthesis

A. R. (2008). The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Investigational New Drugs 26,45—51. 

The result of this biosynthesis is that the product is nicotinic acid mononucleotide rather than free nicotinic acid. Ingested nicotinic acid is converted to nicotinic acid mononucleotide which, in turn, is converted to nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide. If excess nicotinic acid is ingested, it is metabolized into a series of detoxification products (Fig. 4). Physiological metabohtes include /V-methylnicotinamide (19) and A/-methyl-6-pyridone-2-carboxamide (24) (1). 

FIGURE 1.4 Proposed biosynthetic route for the biosynthesis of (A) squalene oxide (squalene-2,3-oxide) via the isoprenoid pathway and (B) triterpene saponins of the dammarane-type and oleanane-type from squalene oxide. PP, diphosphate group GPS, geranyl phosphate synthase FPS, farnesyl phosphate synthase NADPH, nicotinamide adenine dinucleotide phosphate. 

Nicotinate and nicotinamide, together referred to as niacin, are required for biosynthesis of the coenzymes nicotinamide adenine dinucleotide (NAD"") and nicotinamide adenine dinucleotide phosphate (NADP" ). These both serve in energy and nutrient metabolism as carriers of hydride ions (see pp. 32, 104). The animal organism is able to convert tryptophan into nicotinate, but only with a poor yield. Vitamin deficiency therefore only occurs when nicotinate, nicotinamide, and tryptophan are all simultaneously are lacking in the diet. It manifests in the form of skin damage (pellagra), digestive disturbances, and depression. 

The importance of nicotinamide adenine dinucleotides in biochemical pathways is attested by the fact that about 250 enzymes that utilize them as coenzymes are known (B-75MI11001). Nicotinamides play essential roles in the two major types of process that characterize life energy harvestation and biosynthesis. 

Several of the B vitamins function as coenzymes or as precursors of coenzymes some of these have been mentioned previously. Nicotinamide adenine dinucleotide (NAD) which, in conjunction with the enzyme alcohol dehydrogenase, oxidizes ethanol to ethanal (Section 15-6C), also is the oxidant in the citric acid cycle (Section 20-10B). The precursor to NAD is the B vitamin, niacin or nicotinic acid (Section 23-2). Riboflavin (vitamin B2) is a precursor of flavin adenine nucleotide FAD, a coenzyme in redox processes rather like NAD (Section 15-6C). Another example of a coenzyme is pyri-doxal (vitamin B6), mentioned in connection with the deamination and decarboxylation of amino acids (Section 25-5C). Yet another is coenzyme A (CoASH), which is essential for metabolism and biosynthesis (Sections 18-8F, 20-10B, and 30-5A). 

Piericidins are the first compounds obtained by the screening search for insecticidal natural products among microbial metabolites.10 They were isolated from Streptomyces mobaraensis in 1963,11 and many piericidin derivatives have been found in microbial metabolites until now.12 Piericidins are not used as insecticides practically, but are important biological reagents because they have specific inhibitory activity toward the mitochondrial electron transport chain protein nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase (complex I).13 Piericidin Ax (1 in Figure 1) is biosynthesized as a polyketide,14 but genes responsible for its biosynthesis are not yet identified. Total synthesis of piericidins A (1) was reported recently.15... 

Figure 5.3 Outline of the mevalonate pathway for the formation of C5 isoprenoid units. Most research has focused on HMC-CoA reductase (HMCR), the rate-determining step in terpenoid biosynthesis in mammals. P indicates a phosphate moiety. HMC-CoA, 3-hydroxy-3 methylglutaryl coenzyme A NADPH, nicotinamide adenine dinucleotide phosphate (reduced form) SCoA, S-Coenzyme A (to which acetate is attached) CoASH, free coenzyme A.

Ikeda, M., Tsuji, H., Nakamura, S., Ichiyama, A., Nishizuka, Y., and Hayaishi, O. (1965) Studies on the biosynthesis of nicotinamide adenine dinucleotide. II. A role of picolinic carboxylase in the biosynthesis of nicotinamide adenine dinucleotide from tryptophan in mammals. J. Biol. Chem. 240 1395-401. 

Begley TP, Kinsland C, Mehl RA, Osterman A, Dorrestein P. The biosynthesis of nicotinamide adenine dinucleotides in bacteria. Vitam. Horm. 2001 61 103-119. 

Ijichi, H-, Ichiyama, A., and Hayaishi, S. 1966). Studies on the biosynthesis of nicotinamide adenine dinucleotide. J. BrttJ. Orem. 241,3701-3707. 

Various inborn errors of metabolism (Table 25-1) result from deficiencies or absence of some of the enzymes listed in Figure 25-9. Some of these are discussed later in the chapter. The relationship of carbohydrate metabolism to the production of lactate, ketone bodies, and triglycerides is also depicted in Figure 25-9. The pentose phosphate pathway, also known as the hexose monophosphate shunt, is an alternative pathway for glucose metaboUsm that generates the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH), which is used in maintaining the integrity of red blood cell membranes, in lipid and steroid biosynthesis, in hydroxylation reactions, and in other anabolic reactions. The complete picture of intermediary metabolism of carbohydrates is rather complex and interwoven with the metabolism of lipids and amino acids. For details, readers should consult a biochemistry textbook. 

Gatto et al m characterized the mechanism of L-pipecolic acid formation by cyclodeaminase RapL from L-lysine within rapamycin biosynthesis, which is a hybrid NRP—polyketide antibiotic (Figure 25(a)). RapL was characterized by biochemical assays to require cofactor nicotinamide adenine dinucleotide (NAD+) and an oxidative cyclodeamination reaction mechanism corresponding to ornithine cyclodeamination was proposed based on ESI-FTMS analysis of RapL reaction products (Figure 25(b)). 

Biosynthesis of nicotinamide adenine dinucleotides in bacteria 01MI9. Biosynthesis of pyrroloquinoline quinone 01 MI 17. 

The chemistry of the cofactors has provided a fertile area of overlap between organic chemistry and biochemistry, and the organic chemistry of the cofactors is now a thoroughly studied area. In contrast, the chemistry of cofactor biosynthesis is stiU relatively underdeveloped. In this review the biosynthesis of nicotinamide adenine dinucleotide, riboflavin, folate, molyb-dopterin, thiamin, biotin, Upoic acid, pantothenic acid, coenzyme A, S-adenosylmethionine, pyridoxal phosphate, ubiquinone and menaquinone in E. coli will be described with a focus on unsolved mechanistic problems. 

Two cofactors were found to be essential for the production of hydrogenobyrinic acid 60 from precorrin-3A 55, namely SAM, as would be expected, but also reduced nicotinamide adenine dinucleotide phosphate (NADPH, partial structure 59) which was surprising. Scheme 19. Omission of NADPH from the incubation gave a critically important result no 60 was formed but a new pale-yellow product appeared in its place. When a labelled form of this new pigment was incubated with the enzyme system, now with NADPH included, it was specifically converted into hydrogenobyrinic acid 60 in high yield. Clearly, a new intermediate for Bi2-biosynthesis had been found which opened the door to dramatic progress [89]. 

Figure 2 NAD biosynthesis subsystem diagram. Major functional roles are shown by 4-6 letter abbreviations (explained in Table 1) over the colored background reflecting the key aspects or modules (pathways) that comprise NAD biosynthesis in various species. Catalyzed reactions are shown by solid straight arrows, and corresponding intermediate metabolites are shown as abbreviations within ovals Asp, L-aspartate lA, Iminoaspartate Qa, quinolinic acid Nm, nicotinamide Na, nicotinic acid NaMN, nicotinic acid mononucleotide NMN, nicotinamide mononucleotide RNm, N-ribosyInicotinamide NaAD, nicotinate adenine dinucleotide NAD, nicotinamide adenine dinucleotide NADP, NAD-phosphate Trp, tryptophan FKyn, N-formylkynurenine Kyn, kynurenine HKyn, 3-hydroxykynurenine HAnt, 3-hydroxyanthranilate and ACMS, a-amino-/3-carboxymuconic semialdehyde. Unspecified reactions (including spontaneous transformation and transport) are shown by dashed arrows.

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