Nicotinamide, metabolites

N-(2-hydroxyethyl)-nicotinamide, which undergoes further side-chain degradation to nicotinuric acid and, subsequently, nicotinamide and nicotinamide metabolites (e.g., nicotinic acid and N-methylnicotinamide). The nicotinamide derived from nicorandil merges into the endogenous pool of nicotinamide adenine dinucleoside coenzymes. Its elimination half-life is approximately 1 hour. Approximately 30% of nicorandil is excreted into the urine as metabolites, with less than 1% excreted unchanged. 

Abelson, D. and Boyle, A., Photochemistry of a nicotinamide metabolite, N -methyl-4-pyridone-3-carboxamide, Natwre (London), 197,460-462, 1963. 

Rice bran is the richest natural source of B-complex vitamins. Considerable amounts of thiamin (Bl), riboflavin (B2), niacin (B3), pantothenic acid (B5) and pyridoxin (B6) are available in rice bran (Table 17.1). Thiamin (Bl) is central to carbohydrate metabolism and kreb s cycle function. Niacin (B3) also plays a key role in carbohydrate metabolism for the synthesis of GTF (Glucose Tolerance Factor). As a pre-cursor to NAD (nicotinamide adenine dinucleotide-oxidized form), it is an important metabolite concerned with intracellular energy production. It prevents the depletion of NAD in the pancreatic beta cells. It also promotes healthy cholesterol levels not only by decreasing LDL-C but also by improving HDL-C. It is the safest nutritional approach to normalizing cholesterol levels. Pyridoxine (B6) helps to regulate blood glucose levels, prevents peripheral neuropathy in diabetics and improves the immune function. 

Human CYPs are multicomponent enzyme systems, requiring at a minimum the CYP enzyme component and a reductase component to be functional. The reductase requires a reduced nicotinamide cofactor, typically NADPH, and this cofactor must be regenerated to provide a steady supply of reducing equivalents for the reductase. Regeneration is accomplished with a separate substrate and enzyme. Glucose-6-phosphate and glucose-6-phosphate dehydrogenase have been widely used for this purpose. The overall complexity of the reaction mixtures and their cost have been barriers to the widespread use of recombinant human CYPs for metabolite synthesis in the past. 

Hexachloroethane is metabolized by the mixed function oxidase system by way of a two-step reduction reaction involving cytochrome P-450 and either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or cytochrome b5 as an electron donor. The first step of the reduction reaction results in the formation of the pentachloroethyl free radical. In the second step, tetrachloroethene is formed as the primary metabolite. Two chloride ions are released. Pentachloroethane is a minor metabolic product that is generated from the pentachloroethyl free radical. 

In the past decade, a large number of studies emphasized the heterogeneous scale-free degree distribution of metabolic networks Most substrates participate in only a few reactions, whereas a small number of metabolites ( hubs ) participate in a very large number of reactions [19,45,52]. Not surprisingly, the list of highly connected metabolites is headed by the ubiquitous cofactors, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and nicotinamide adenine dinucleotide (NAD) in its various forms, as well as by intermediates of glycolysis and the tricarboxylic acid (TCA) cycle. 

FIGURE I A reconstructed extracted ion chromatogram of nicotinic acid and its six metabolites under HILIC conditions. Column Hypersil silica (4.6 X 50 mm) at a flow rate of 4 mL/min. Mobile phase A is water, mobile phase B is acetonitrile, both containing 1% formic acid. Gradient is 0.01-0.25 min 90% B to 65% B 0.25-0.90 min 65% B to 50% B. NA nicotinic acid NAM nicotinamide NUA nicotinuric acid 2-PY l-methyl-2-pyridone-5-carboxamide l-MNAM I-methyl-nicotinamide NAMO nicotinamide-N-oxide 4-PY l-methyl-4-pyridone-5-carboxamide. (Reprinted with permission from Reference 20.)... 

Note that this overall reaction requires three coenzymes that we encountered as metabolites of vitamins in chapter 15 NAD+, derived from lucotiiuc acid or nicotinamide FAD, derived from riboflavin and coenzyme A(CoASH), derived from pantothenic acid. In the overall process, acetyl-SCoA is oxidized to two molecules of carbon dioxide with the release of CoASH. Both NAD+ and FAD are reduced to, respectively, NADH and FADH2. Note that one molecule of guanosine triphosphate, GTP, functionally equivalent to ATP, is generated in the process. 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

An enzyme reactor with immobilized 3 -hydroxysteroid dehydrogenase has been successfully used for the analysis of residues of 17 -methyltestosterone in trout by high-performance liquid chromatography (HPLC) (269). Following their separation by reversed-phase chromatography, the major tissue metabolites of 17 -methyltestosterone, namely 5 -androstane-17 -methyl-3, 17 -diol, and 5 -androstane-17 -methyl-3, 17 -diol, were enzymatically modified in the presence of a coreactant, nicotinamide-adenine dinucleotide (NAD), to the corresponding ketone. The position at 3 was enzymatically oxidized, and NADH, the reduced form of NAD, was produced as a coproduct and subjected to fluorescence detection. Reoxidation of NADH to NAD provides the possibility for electrochemical detection. 

Reduced flavins, unlike reduced nicotinamides, are reactive towards molecular oxygen, and an intermediate produced in this reaction is a more potent oxygenating agent than molecular oxygen is itself. A number of enzymes have evolved which utilize this intermediate to oxygenate certain metabolites. These reactions usually entail monooxygenation (Scheme 5). There are, however, at least two examples of dioxygenation that have been reported... 

Why do we need vitamins Early clues came in 1935 when nicotinamide was found in NAD+ by H. von Euler and associates and in NADP+ by Warburg and Christian. Two years later, K. Lohman and P. Schuster isolated pure cocarboxylase, a dialyz-able material required for decarboxylation of pyruvate by an enzyme from yeast. It was shown to be thiamin diphosphate (Fig. 15-3). Most of the water-soluble vitamins are converted into coenzymes or are covalently bound into active sites of enzymes. Some lipid-soluble vitamins have similar functions but others, such as vitamin D and some metabolites of vitamin A, act more like hormones, binding to receptors that control gene expression or other aspects of metabolism. 

In addition to the oxazoles O-isopentenylhalfordinol (19) (72), 0-geranylhal-fordinol (21) (75), and 2-pyridyl-5-(3-methoxy-4,5-methylenedioxy)phenyl ox-azole (24) (13), Amyris plumieri produces a number of novel chromenylated tyramides 41-43 and the (3-styrylamide 44 (12-14, 18). The only other iso-lable metabolites from this plant were nicotinamide (45) and 4-(3,3-dimethyl) allyloxybenzoic acid (46) (12, 18). These two latter compounds are thought to... 

Pharmacokinetics Niacin is administered orally. It is converted in the body to nicotinamide, which is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD+). Niacin, its nicotinamide derivative and other metabolites are excreted in the urine. [Note Nicotinamide alone does not decrease plasma lipid levels.]... 

The essential difference between nicotinamide and flavin is in the nature of the acceptor site, i.e., CH for nicotinamide as compared with N for flavoquinone. This explains why 5-deazaflavins appear to be interesting flavin (anti)metabolites since they are expected to be functional analogs of nicotinamide, exhibiting at the same time the steric shape of a flavin. Indeed it turns out that incorporation of 5-deazaflavin into apo-flavoproteins blocks the electron transfer and oxygen activation properties (32,33,34,35,36). Retaining at least partially the (de) hydro-... 

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... 

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