Nicotinamide coenzyme biosynthesis

Keys, L. D., and G. A. Hamilton. 1987. The mechanism for the conversion of a-amino-P-carboxymucon-ate-8-semialdehyde to quinolinate, an apparent nonenzymic step in the biosynthesis of the nicotinamide coenzymes from tryptophan. J. Am. Chem. Soc. 109 2156-2163. 

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). 

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 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). 

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.

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. 

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. 

In contrast to our understanding of the biosynthesis of cofactors, relatively little is known about cofactor degradation. Some previous research has been carried out to identify intermediates on these catabolic pathways, but very little information is available on the genes involved and on the enzymol-ogy. In this chapter we summarize our current understanding of the pyridoxal phosphate, riboflavin, heme, thiamin, biotin, nicotinamide adenine dinucleotide (NAD), folate, lipoate, and coenzyme A catabolic pathways in all life-forms and discuss mechanistic aspects of the most interesting catabolic reactions. 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

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. 

This reaction is the initial step of the biosynthesis of the coenzyme nicotinamide-adenine dinucleotide (NAD) from tryptophan in mammals. 

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. 

Figure 2. Biosynthesis of plasmalogens in mammalian tissues. Enzymes (1) dihydroxyacetone phosphate acyltransferase (2) 1-acyldihydroxyacetone phosphate synthase (3) 1-alkyldihydroxyacetone phosphate oxidoreductase (4) l-alkyl-5n-glycero-3-phosphate acyltransferase (5) 1-afkyl 2-acyl-5w-glycero-3-phosphohydrolase (6) CDP-ethanolamine transferase (7) l-alkyl-2-acyl-5w-glycero-3-phosphoethanolamine desaturase (8) methyltransferases and base-exchange enzymes. CDP-ethanolamine, cytidine diphosphoethanolamine. CMP, cytidine monophosphate. CoA, coenzyme A. DHAP, dihydroxyacetone phosphate. NADH, nicotinamide adenine dinucleotide, reduced form. NAD, nicotinamide adenine dinucleotide, oxidized form. Pi, phosphate.

In the rapid biosynthesis of DPN induced by the injection of nicotinamide, the increase in coenzyme is associated with a parallel rise of the liver acid-soluble adenine, nicotinamide, ribose, and phosphate 303). No changes in the concentrations of nucleic acids, or of 5 -adenylic acid, ADP, and ATP have been detected. These results show that formation of the newly synthesized pyridine coenz3rme does not occur at the expense of the... 

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

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