Pyridine nucleotides, metabolic functions

Liver cells contain two different but closely related enzymes glycerol phosphate dehydrogenase which is specific for NAD, and acylglycerol phosphate dehydrogenase, which is NADP specific. Both enzymes have B stereospecificity for the pyridine nucleotide 93. They apparently have different metabolic functions. 

The pyridine nucleotide-disulfide oxidoreductases, lipoamide dehydrogenase (4), glutathione reductase (5), and thioredoxin reductase (6-8) share so many properties in common that they will be compared and contrasted before being considered separately. As their group name implies, they catalyze the transfer of electrons between pyridine nucleotides and disulfides. In spite of their similarities they function in widely divergent metabolic roles. 

The pyridine nucleotides are the functional form of nicotinic acid, but still comparatively little work has been done on their relation to tryptophan-nicotinic acid metabolism. Two possibilities must be considered the pyridine nucleotides may be formed from tryptophan without intermediacy of nicotinic acid and only give nicotinic acid on breakdown, or nicotinic acid first formed from tryptophan may be incorporated into pyridine nucleotides. The latter now seems the more likely possibility, though the former has not been excluded. 

Methylation is rarely of quantitative importance in the metabolism of xenobiotics. The methyl group is transferred from the nucleotide S-adenosyl-L-methionine (SAM) by means of a methyltransferase. The functional groups that undergo methylation include primary, secondary and tertiary amines, pyridines, phenols, catechols, thiophenols. The aza-heterocycle pyridine is metabolized to the A-methylpyridin-ium ion, which is more toxic than pyridine itself (Figure 33.18). The binding properties of the ionized metabolite are disturbed by the loss of its hydrophobic feature, resulting from the polarity inversion. 

Thus, the reduced form of cytochrome P-450 functions as the oxygenactivating biocatalyst of a wide variety of mixed-function oxidations by vertebrate tissues effecting biosynthesis and catabolism of steroid hormones, bile acid formation, and the metabolism of drugs and other xeno-biotics (16). Since reduced pyridine nucleotides do not react directly with hemoproteins, the hydroxylase systems must include components that mediate the electron transport from TPNH to cytochrome P-450. There also must be distinctive diflFerences in composition causing the substrate specificity of the oxygenations. 

This discussion will be limited to aerobic hydroxylation reactions. As already mentioned, it is a reaction which appears to be restricted to the metabolism of rather inert molecules. The reason for this is not apparent, but it may be because the reaction is energetically expensive for the cell. If, in the hydration type of hydroxylation reaction, a pyridine nucleotide functions as the hydrogen acceptor, the subsequent reoxidation of the DPNH or TPNH over the flavin-cytochrome hydrogen transport system could be coupled to the synthesis of 3 moles of ATP per mole of DPNH oxidized. In the aerobic type of hydroxylation reaction, utilizing TPNH as the electron donor, the oxidation of the TPNH is apparently not coupled to high-energy phosphate-bond synthesis and the cell therefore loses the equivalent of three ATP s. 

The antagonists of nicotinic acid are 6-aminonicotinamide and, less potent, 3-acetylpyridine and pyridine-3-sulfonic acid (H15, J4). Nicotinamide has also been reported to be effective in experimental cancer (S3). It is supposedly converted to nonphysiological nucleotide analogs of NAD and NADP because it becomes attached to available apo-dehydrogenase the resulting enzyme cannot function in hydrogen and electron-transfer reactions essential to normal cellular metabolism (D7). 

An important group of mixed function oxidases which occur in all types of organism and which are critical in the metabolism of the aromatic amino adds and other aromatic substrates are the aromatic hydroxylases. Their mode of action, the overall stoichiometry of which is represented in the sequence below, results in the introduction of a phenolic hydroxyl group in an aromatic ring system and has been the subject of intensive study. Pyridine and flavin nucleotides, cytochromes, metals (Fe, Cu), ascorbate and pteridine derivatives (H2X) may serve as electron donors. Most, but not all, of these en2yme reactions require transition metal ions for full activity. 

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