Aminocarboxymuconic semialdehyde

Even without induction of tryptophan dioxygenase, impairment of the activity of either enzyme may impair the onward metabolism of kynurenine and thus reduce the accumulation of aminocarboxymuconic semialdehyde and synthesis of NAD. 

The result of this is that at low rates of flux through the kynurenine pathway, which result in concentrations of aminocarboxymuconic semialdehyde below that at which picolinate carboxyltise is saturated, most of the flux will be by way of the enzyme-catalyzed pathway, leading to oxidation. There will be little accumulation of eiminocarboxymuconic semitddehyde to undergo nonenzymic cyclization. As the rate of formation of aminocarboxymuconic semialdehyde increases, and picolinate carboxylase nears saturation, there will be an increasing amount available to undergo the nonenzymic reaction and onward metabolism to NAD. Thus, there is not a simple stoichiometric relationship between tryptophan and niacin, and the equivtilence of the two coenzyme precursors will vary as the amount of tryptophtm to be metabolized and the rate of metabolism vary. 

As might be expected, the synthesis of NAD from tryptophan is inversely related to the activity of picolinate carboxylase. Inhibition with pyrazinamide results in increased availability of aminocarboxymuconic semialdehyde, and hence increased NAD formation. Equally, activation of picolinate carboxylase results in reduced availability of aminocarboxymuconic semialdehyde for cyclization, and hence a reduced formation of NAD. 

The activities of three enzymes, tryptophan dioxygenase, kynurenine hydroxylase and kynureninase, affect the rate of formation of aminocarboxymuconic semialdehyde, as may the rate of uptake of tryptophan into the liver. 

The activities of both kynurenine hydroxylase and kynureninase are only slightly higher than that of tryptophan dioxygenase under basal conditions, and increased tryptophan dioxygenase activity in response to glucocorticoid action is accompanied by increased accumulation and excretion of kynurenine, hydroxykynurenine and their transamination products, kynurenic and xanthurenic acids. Impairment of the activity of either enzyme may impair the onward metabolism of kynurenine and so reduce the accumulation of aminocarboxymuconic semialdehyde, and hence the synthesis of NAD. 

Figure 2 NAD metabolism. Tip = tryptophan, 3-HK = 3-hydroxykynurenine, 3-HA = 3-hydroxyanthranilic acid, ACMS = a-amino-P-carboxymuconate- -semialdehyde, AMS = a-aminomuconate- -semialdehyde, NaMN = nicotinic acid mononucleotide, NMN = nicotinamide mononucleotide, NaAD = nicotinic acid adenine dinucleotide. For other abbreviations, see Figure 1. (1) tryptophan oxygenase [EC 1.13.11.11], (2) formy-dase [EC 3.5.1.9], (3) kynurenine 3-hydroxylase [EC 1.14.13.9], (4) kynureninase [EC 3.7.1.3], (5) 3-hydroxyanthranilic acid oxygenase [EC 1.13.11.6], (6) nonenzymatic, (7) aminocarboxymuconate-semialdehyde decarboxylase [EC 4.1.1.45], (8) quinolinate phos-phoribosyltransferase [EC 2.4.2.19], (9) NaMN adenylyltransferase [EC 2.7.2.18], (10) NAD synthetase [EC 6.3.5.1], (11) NAD kinase [EC 2.7.1.23], (12) NAD" glycohydro-lase [EC 3.2.2.5], (13) nicotinamide methyltransferase [EC 2.2.1.1], (14) 2-Py-forming MNA oxidase [EC 1.2.3.1], (15) 4-Py-forming MNA oxidase [EC number not given], (16) nicotinamide phosphoribosyltransferase [EC 2.4.2.12], (17) NMN adenylytransferase [EC 2.7.71], (18) nicotinate phosphoribosyltransferase [EC 2.4.2.11], (19) nicotinate methyltransferase [EC 2.7.1.7], and nicotinamidase [EC 3.5.1.19]. Solid line, biosynthesis dotted line, catabolism.

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