Nicotinamide adenine dinucleotide phosphate biosynthesis

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. 

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.

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. 

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]. 

Nicotinamide adenine dinucleotide (NAD) is the coenzyme form of the vitamin niacin. Most biochemical reactions require protein catalysts (enzymes). Some enzymes, lysozyme or trypsin, for example, catalyze reactions by themselves, but many require helper substances such as coenzymes, metal ions, and ribonucleic acid (RNA). Niacin is a component of two coenzymes NAD, and nicotinamide adenine dinucleotide phosphate (N/kDP). NAD (the oxidized form of the NAD coenzyme) is important in catabolism and in the production of metabolic energy. NADP (the oxidized form of NADP) is important in the biosynthesis of fats and sugars. 

The enzyme dihydrofolate reductase (DHFR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH) reduction of folate to dihydrofolate and tetrahydrofolate, the class of cofactors used in the biosynthesis of thymidylate and hence DNA. Inhibition of DHFR prevents cell growth and kills cells, so... 

Whereas catabolism involves oxidation of starting molecnles, biosynthesis or anabolism involves reduction reactions, hence the need for a reducing agent or hydrogen donor, which is usually NADP (nicotinamide adenine dinucleotide phosphate). These catalysts are known as coenzymes and the most widely occurring is coenzyme A (CoA), made up of ADP (adenosine diphosphate) and pantetheine phosphate. 

Fig. 3.6 Revised pathway for saxitoxin biosynthesis and the putative functions of sxt genes (adapted from Kellmann et al. [27]). Abbreviations used were ACP acyl carrier protein, ACTF acetyltransferase, AONS 8-amino-7-oxononanoate synthase, CARBP carbamoyl phosphate, MTF methyltransferase, NAD(P) nicotinamide adenine dinucleotide (phosphate)...

Figure 5. Ceramide biosynthesis (modified from Kolter and Sandhoff, 1999). PLP, pyridoxal phosphate. NADPH, nicotinamide adenine dinucleotide phosphate.

Although it was known that the intermediates of the yS-oxidation cycle are chaimelled towards PHA biosynthesis, only recently the precursor sources were identified. In A. caviae, the y3-oxidation intermediate, trans-2-tnoy -CoA is converted to (R)-3-hydroxyacyl-CoA via (R)-specific hydration catalysed by an (R)-specific enoyl-CoA hydratase [125, 126]. Subsequently, Tsuge and co-workers [127] reported the identification of similar enoyl-CoA hydratases in Pseudomonas aeruginosa. In the latter case, two different enoyl-CoA hydratases with different substrate specificities channelled both SCL and MCL enoyl-CoA towards PHA biosynthesis. In recombinant . coli it was further shown that 3-ketoacyl-CoA intermediates in the )8-oxidation cycle can also be channelled towards PHA biosynthesis by a nicotinamide adenine dinucleotide phosphate dependent (NADPH-dependent) 3-ketoacyl-ACP reductase [128]. A similar pathway was also identified in P. aeruginosa [129]. In addition, it was also reported that the acetoacetyl-CoA reductase (PhaB) of R. eutropha can also carry out the conversion of 3-ketoacyl-CoA intermediates in Pathway II to the corresponding (R)-3-hydroxyacyl- CoA in E. coli [130]. The results clearly indicate that several channelling pathways are available to supply substrates from the y3-oxidation cycle to the PHA synthase. This explains why it was not possible to obtain mutants that completely lack PHA accumulation ability, unless the mutation occurred in the PHA synthase gene [131]. 

NADPH (nicotinamide adenine dinucleotide phosphate) A reduced coenzyme used in biosynthesis. 

Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate (H2F) by nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form 5,6,7,8-telrahydrofolate (H4F), a key step in furnishing the parental cofactor needed for de novo pyrimidine and purine biosynthesis. The enzyme has been the target of antitumor and antimicrobial drugs. A complete Idnelic scheme (Fig. 6) obtained primarily throngh transient kinetics has been described for the enzyme bosaEscherichia coli as well as other sources and provides a second case smdy as to how to define the catalytic process. 

The direct oxidation of glucose via pentoses is of significance for the formation of pentoses (and indirectly for nucleic acid synthesis). Nicotinamide-adenine dinucleotide phosphate (NADP) is the hydrogen acceptor here. The reduced form , NADPH2, is necessary for many synthetic processes, e.g., for the synthesis of fatty acids, for the biosynthesis of cholesterol, and for hydroxylation reactions. The direct oxidation of glucose to pentoses, therefore, has this second function It provides the necessary reduction equivalents for other anabolic processes. It is not a source of energy. 

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. 

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