Nicotinamide, biosynthesis

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). 

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

The biosynthesis and metabolism of nicotinic acid in disease has received little attention metabolic studies deal mainly with normal animals and man (01, R5). After a tryptophan load dose, the main catabolites in the urine are nicotinuric acid, N1-methylnicotinamide, nicotinamide, quinolinic acid, kynurenine, 6-pyridone, anthranilic acid, and 3-hydroxyanthranilic acid. These excretory products were estimated... 

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. 

A special metabolic task carried out by the nucleus is biosynthesis of NADT The immediate precursor of this coenzyme, nicotinamide mononucleotide (NMN""), arises in the cytoplasm and is then transported into the nucleolus, where it is enzymatically converted into the dinucleotide NADT Finally, NAD"" then returns to the cytoplasm. 

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 NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Srr2 activity in mammalian cells. The Journal of Biological Chemistry, 279, 50754—50763. 

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). 

Tanno, O. et al., Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier, Br. J. Dermatol., 143, 524, 2000. 

Reactions (10.9) and (10.10) are catalyzed by flavokinase and FMN pyrophos-phorylase, respectively. For the structures of FMN and FAD, see Chapter 6. The biosynthesis of NAD+ from nicotinamide is shown in Figure 10.12. An additional phosphorylation step with ATP is required to form NADP+. If one... 

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. 

Bacteria and plants use aspartate (54) and dihydroxyacetone phosphate (50) as precursors for the biosynthesis of nicotinamide via quinolinic acid (53, Fig. 6B) (33). 

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

Purines and pyrimidines are derived largely from amino acids. The biosynthesis of these precursors of DNA, RNA, and numerous coenzymes will be discussed in detail in Chapter 25. The reactive terminus of sphingosine, an intermediate in the synthesis of sphingolipids, comes from serine. Histamine, a potent vasodilator, is derived from histidine by decarboxylation. Tyrosine is a precursor of the hormones thyroxine (tetraiodothyronine) and epinephrine and of melanin, a complex polymeric pigment. The neurotransmitter serotonin (5-hydroxytryptamine) and the nicotinamide ring of NAD + are synthesized from tryptophan. Let us now consider in more detail three particularly important biochemicals derived from amino acids. 

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. 

This spectacular bleaching effect is discussed in other chapters of this work, such as the N-benzylideneamino heterocycles of the Shell workers, the nicotinamides of Stauffer, the pyridazines of American Cyanamid and the furanones of Chevron. Various aspects of carotenoid biosynthesis inhibition have been presented in other places (27,31). however, we see here some of the exciting new chemistry associated with these powerful compounds. 

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