Nicotinamide ring

Niacin was discovered as a nutrient during studies of pellagra. It is not strictly a vitamin since it can be synthesized in the body from the essential amino acid tryptophan. Two compounds, nicotinic acid and nicotinamide, have the biologic activity of niacin its metabolic function is as the nicotinamide ring of the coenzymes NAD and NADP in oxidation-reduction reactions (Figure 45-11). About 60 mg of tryptophan is equivalent to 1 mg of dietary niacin. The niacin content of foods is expressed as mg niacin equivalents = mg preformed niacin + 1/60 X mg tryptophan. Because most of the niacin in cereals is biologically unavailable, this is discounted. 

When the enzyme alcohol dehydrogenase converts acetaldehyde to ethanol, NADH acts as a reducing agent by transferring a hydride from C4 of the nicotinamide ring to the carbonyl group of acetaldehyde. 

The free energy associated with the hydride ion transfer from C4 of the nicotinamide ring to C6 of the pteridine ring was computed in a manner... 

Figure 10. The ternary complex of the enzyme dihydrofolate reductase, the substrate and the cofactor during the transition state of the hydride ion transfer. The enzyme backbone atoms are shown alone for clarity and are colored blue. The substrate is shown in yellow and the cofactor is in red. The bond colored in light blue indicates the hydride ion being shared by both the cofactor and the substrate before the transfer to the substrate. Water molecules around the residue pteridine of the substrate and the nicotinamide ring of the cofactor alone are shown and colored in light blue. The yellow spheres represent the sodium ions and the pink spheres the chloride ions.

The pyridine nucleotide dehydrogenase reactions fall into two large groups those which transfer hydrogen from or to the A (or pro R) side of the 4 position of the nicotinamide ring, and those which use the B (or pro S) side 1.64,65),... 

In the classical procedures W, the 5-T or D-labeled mevalonate is converted enzymatically to farnesol, which is then oxidized to famesal by liver alcohol dehydrogenase. This enzyme transfers the pro-R hydrogen of C—1 of ethanol or geraniol (or farnesol) to the 4 pro R position of the nicotinamide ring of NAD. 

Isotope effects on both the carbon and hydrogen of the breaking C-H bond have been measured. However, for this reaction both forward and reverse commitments are sizable so the three equations corresponding to Equation 11.48 have four unknowns the forward and reverse commitments and two intrinsic isotope effects. Measurements of the secondary deuterium kinetic isotope effect (at position 4 of nicotinamide ring of NADP+) and the carbon kinetic isotope effect with the secondary position deuterated introduce two additional equations, but only one more unknown ... 

Human type II inosine monophosphate dehydrogenase catalyses NAD-dependent conversion of inosine monophosphate (IMP) into xanthosine monophosphate (XMP) measurements of the primary kinetic isotope effect using [ H]IMP suggest that both substrates (IMP and NAD) can dissociate from the enzyme-substrate complex therefore, the kinetic mechanism is not ordered. NMR studies indicate hydride transfer to the B or pro-S face of the nicotinamide ring of NAD, while kinetic studies suggest... 

The pyridine nucleotides NAD and NADP always function in unbound form. The oxidized forms contain an aromatic nicotinamide ring in which the positive charge is delocalized. The right-hand example of the two resonance structures shown contains an electron-poor, positively charged C atom at the para position to nitrogen. If a hydride ion is added at this point (see above), the reduced forms NADH or NADPH arise. No radical intermediate steps occur. Because a proton is released at the same time, the reduced pyridine nucleotide coenzymes are correctly expressed as NAD(P)H+HT... 

D. Amino Acids Important in Binding the Nicotinamide Ring and Carboxamide Moiety... 

Both 11P-HSD types 1 and 2 contain residues in the C-terminal half that interact with the nicotinamide ring and carboxamide moiety to limit rotations about the N-glycosidic bond. These intersections are important in positioning the cofactor for proS hydride transfer at C4. 

In 1 ip-HSD-1, cysteine-213 stabilizes the nicotinamide ring threonine-220 and threonine-222 stabilize the carboxamide moiety. In 11 P-HSD-2, there are more interactions proline-262, phenylalanine-265, threonine-267, serine-... 

Biological Reduction by Alcohol Dehydrogenases. Bioreductions of atoms doubly bound to oxygen are consistent with a mechanism for attack that would involve a nucleophilic form of hydrogen. Indeed such bioreductants occur in organisms. The reactive portion of one such reductant, the nicotinamide ring of NADH or NADPH (referred to as NAD(P)H), is ... 

Nicotinamide adenine dinucleotide (NAD+ in its oxidized form) and its close analog nicotinamide adenine dinucleotide phosphate (NADP+) are composed of two nucleotides joined through their phosphate groups by a phosphoanhydride bond (Fig. 13-15a). Because the nicotinamide ring resembles pyridine, these compounds are sometimes called pyridine nucleotides. The vitamin niacin is the source of the nicotinamide moiety in nicotinamide nucleotides. 

Both coenzymes undergo reversible reduction of the nicotinamide ring (Fig. 13-15). As a substrate molecule undergoes oxidation (dehydrogenation), giving up two hydrogen atoms, the oxidized form of the nucleotide (NAD+ or NADP+) accepts a hydride ion ( H, the equivalent of a proton and two electrons) and is transformed into the reduced form (NADH or NADPH). The second proton removed from the substrate is released to the aqueous solvent. The half-reaction for each type of nucleotide is therefore... 

FIGURE 13-15 NAD and NADR (a) Nicotinamide adenine dinucleotide, NAD +, and its phosphorylated analog NADP+ undergo reduction to NADH and NADPH, accepting a hydride ion (two electrons and one proton) from an oxidizable substrate. The hydride ion is added to either the front (the A side) or the back (the B side) of the planar nicotinamide ring (seeTable 13-8). (b)The UV absorption spec-... 

Figure 15-4 The nicotinamide ring of NADH in a syn boat conformation suitable for transfer of an axially oriented pro-R hydrogen atom from its A face as H-. The flow of electrons is shown by the solid arrows. The dashed arrows indicate competing resonance which favors planarity of the ring and opposes the H transfer. Hydrogen bonds from the protein to the carboxamide group (dashed lines) affect both this tendency and the conformation of the nucleotide.

Figure 15-5 Structure of the complex of horse liver alcohol dehydrogenase with NAD+ and the slow substrate p-bromobenzyl alcohol. The zinc atom and the nicotinamide ring of the bound NAD+ are shaded. Adjacent to them is the bound substrate. Courtesy of Bryce Plapp. Based on Ramaswamy et al.53...

---