Nicotinamide chemical structure

Oxidation of P-nicotinamide adenine dinucleotide (NADH) to NAD+ has attracted much interest from the viewpoint of its role in biosensors reactions. It has been reported that several quinone derivatives and polymerized redox dyes, such as phenoxazine and phenothiazine derivatives, possess catalytic activities for the oxidation of NADH and have been used for dehydrogenase biosensors development [1, 2]. Flavins (contain in chemical structure isoalloxazine ring) are the prosthetic groups responsible for NAD+/NADH conversion in the active sites of some dehydrogenase enzymes. Upon the electropolymerization of flavin derivatives, the effective catalysts of NAD+/NADH regeneration, which mimic the NADH-dehydrogenase activity, would be synthesized [3]. 

The nicotinamide coenzymes are involved as proton and electron carriers in a wide variety of oxidation and reduction reactions. Before their chemical structures were known, NAD and NADP were known as coenzymes I and II. Later, when the chemical nature of the pyridine ring of nicotinamide was discovered, they were called diphosphopyridine nucleotide (DPN = NAD) and triphospho-pyridine nucleotide (TPN = NADP). The nicotinamide nucleotide coenzymes are sometimes referred to as the pyridine nucleotide coenzymes. 

Cummins, P., Geeady, J. (1989) Mechanistic Aspects of Biological Redox Reactions Involving NADH 1 ab initio Quantum Chemical Structure of the 1-Methyl-nicotinamide and 1-Methyl-Dihydronicotinamide Coenzyme Analogues, J. Mol. Struct. (Theochem) 183, 161-174. 

On the other hand, NAD (nicotinamide adenine dinucleotide), known as coenzyme I and II, and NADP (nicotinamide adenine dinucleotide phosphate) are derivatives of nicotinamides. The chemical structures of NAD, NADP, and the reduced form of these alkaloids, NADH and NADPH (nicotinamide adenine dinucleotide phosphate reduced), are shown. Isonicotinic acid hydrazide (INH or isoniazid) is a synthetic derivative of nicotinic acid and has potent antibacterial activity against Mycobacterium tuberculosis (Section 13.2) [1,2]. 

Chemical structure (Figure 8). Nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (pyridine-3-carboxamide), NAD (nicotinamide adenine dinucleotide), NADP (nicotinamide adenine dinucleotide phosphate). 

Definitive eviderice regarding the chemical structure of the photoadduct came from mass spectrometric and nuclear magnetic resonance (NMR) measurements. The labeled tripeptide, Val-X-Tyr (residues 147-149), was isolated from fragment A irradiated in the presence of either unlabeled NAD or NAD containing [ C] or [ N] within the nicotinamide moiety. Mass spectra of these peptides were taken following fast atom... 

The chemical structure of NADX, as derived from H and C NMR measurements, appears to be consistent with the following formula ADPR-NH-CH=C(CH0)-C0NH2. As one can see, only the nicotinamide moiety has been modified by 202, the remaining part (adenosinedi-phosphoribosyl moiety) being still intact. 

The two oxidation states of (17) that are relevant in biopterin-dependent redox reactions are the four-electron and two-electron reduced forms, tetrahydrobiopterin (19) and p-quinonoid dihydrobiopterin (20), respectively. The oxidation state between these two, i.e. a radical, may also be relevant though it has not been detected as an intermediate in enzymatic reactions. Structurally, pteridines and flavins are rather similar and hence show similar chemical behavior in many respects. As a redox coenzyme, (19) is not encountered nearly as frequently as nicotinamides or flavins. It is, however, the cofactor of three very... 

In the balanced chemical equation for glycolysis, two molecules of NAD+ are converted to two molecules of NADH and two protons. The structure of NAD+ (nicotinamide adenine dinucleotide) is given in Fig. 11.1. This is a reduction reaction, and the NAD+, an enzyme cofactor, has accepted the equivalent of H (a hvdride... 

The structure of the oxidized form of nicotinamide adenine dinucleotide is shown in Figure 15.3. The only portion of the coenzyme that undergoes chemical change in the reaction is the substituted pyridine ring of the nicotinamide unit (shown in red in Figure 15.3). If the remainder of the coenzyme molecnle is represented by R, its role as an oxidizing agent is shown in the equation... 

In a manner similar to the structures of the nicotinamide cofactors, the flavin cofactors FMN/FMNH2 and FAD/FADH2 also have structures that resolve into a chemically reactive unit, the flavin nucleus, and a large ancillary structure that has the function of binding the cofactor in a specific orientation to the host enzyme, as emerges from Fig. 4.2. Here again the flavin nucleus and thus the strictly chemical properties are common to the two coenzymes, which differ in the ancillary part of the structure. 

In such a case, a model compound need contain only the chemically significant features of the non-anchor portion of the natural species. One may then enjoy the convenience of structures that are smaller, easier to synthesize and modify, and cheaper. Figure 4.4 illustrates some of the ways in which these opportunities have been seized in model studies for the nicotinamide cofactors. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

Electron-transfer (ET) reactions play a central role in all biological systems ranging from energy conversion processes (e.g., photosynthesis and respiration) to the wide diversity of chemical transformations catalyzed by different enzymes (1). In the former, cascades of electron transport take place in the cells where multicentered macromolecules are found, often residing in membranes. The active centers of these proteins often contain transition metal ions [e.g., iron, molybdenum, manganese, and copper ions] or cofactors as nicotinamide adenine dinucleotide (NAD) and flavins. The question of evolutionary selection of specific structural elements in proteins performing ET processes is still a topic of considerable interest and discussion. Moreover, one key question is whether such stmctural elements are simply of physical nature (e.g., separation distance between redox partners) or of chemical nature (i.e., providing ET pathways that may enhance or reduce reaction rates). 

Figure 8.2 Malate Dehydrogenase (MDH). (a) Reversible reaction catalyzed by MDH where NADH is nicotinamide adenine dinucleotide, reduced form (b) ribbon display structure of MDH (porcine heart) (side view) (pdb 4mdh). The homo-dimeric protein consists of two polypeptides chains (yellow and red), with nicotinamide adenine dinudeotide (NAD+) in both independent catalytic sites illustrated in a ball and stick (blue) representation (c) chemical illustration of the tricarboxylic acid cycle (TCA) to demonstrate the importance of MDH catalysis in cycle closure. Enzyme abbreviations are PDH, pyruvate dehyrogensase CS, citrate synthase.

---