The Catabolism of Tryptophan

The enzyme indoleamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, kynurenine is then converted to quinolinic acid via the intermediate 3-HK by the enzyme kynurenine hydroxylase. Both IDO and kynurenine hydroxylase are induced by the type-1 cytokine IFN-y. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation, the activation of the type-1 immune response and the regulation of the tryptophan metabolism (Mellor and Munn, 1999). It induces a halt in the lymphocyte cell cycle due to the catabolism of tryptophan (Munn et al., 1999). In contrast to the type-1 cytokines, the type-2 cytokines IL-4 and IL-10 inhibit the IFN-y-induced IDO-mediated tryptophan cataboUsm (Weiss et al., 1999). IDO is located in several cell types including monocytes and microglial cells (Alberati et al., 1996). An IFN-y-induced, IDO-mediated decrease of CNS... 

Oxygenases catalyze reactions in which an oxygen atom or molecule is incorporated into organic substrates. They may therefore be monooxygenases or dioxygenases. An example of a dioxygenase is tryptophan-2,3-dioxygenase (a heme enzyme), which participates in the catabolism of tryptophan (Chapter 17) ... 

Figure 4.1 reveals a number of enzymes that are directly involved at different steps in the catabolism of tryptophan. 

The data indicate that hydroxykynureninase, an enzyme with high preference for hydroxykvTiurenine as substrate when compared with kynurenine, is involved in the synthesis of 3-hydroxyamhranilic acid (3-HA). 3-HA is well known as an intermediate in the catabolism of tryptophan, and in eukaryotes it serves as precursor of nicotinic acid... 

Two enzyme systems have been discovered that initiate the catabolism of tryptophan and lead to the products shown in Fig. 13. These are tryptophan oxidase-peroxidase and kynureninase. Their roles in the catabolic process will be discussed below. 

Among the most interesting of the biological reactions of tryptophan is its conversion to nicotinic acid. In the vertebrates, at any rate, this is a truly anabolic process which serves the end of providing source material for the synthesis of DPN and TPN. The discussion of this pathway of metabolism is contained in the chapter. Synthetic Processes Involving Amino Acids. Conversion to nicotinic acid can not be the major pathway for the catabolism of tryptophan. Based on the capacity of fed tryptophan to prevent symptoms of niacin deficiency in animals, it can be calculated that only 1% or 2% is thus converted in man and the primates. In the rat the conversion may amount to as much as 10%. 

Metabolism of Tryptophan. The catabolism of tryptophan is interesting since it leads to the biosynthesis of a vitamin, nicotinamide. It appears contradictory to state that a vitamin is formed by an organism, but nicotinamide deficiency can indeed be demonstrated only with the concurrent deficiency of vitamin Be. Tryptophan largely replaces the vitamin even in man. 

The catabolism of tryptophan seems to have many steps in common with the formation of nicotinamide. The amino nitrogen is not attacked initially, but instead the indole ring is opened up by tryptophan pyrrolase (an iron-porphyrin enzyme). Just as in other cases of oxidative ring opening (cf. Chapt. X-7), the double bond is split and each new end receives one oxygen atom. In this way N-formylkynurenine is formed it is then hydrolyzed to formate and kynurenine. 

Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydrox5dryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOa), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid...

Returning to the major tryptophan catabolic pathway, marked by green arrows in Fig. 25-11, formate is removed hydrolytically (step c) from the product of tryptophan dioxygenase action to form kynurenine, a compound that is acted upon by a number of enzymes. Kynureninase (Eq. 14-35) cleaves the compound to anthranilate and alanine (step d), while transamination leads to the cyclic kynurenic acid (step e). Hie latter is dehydroxylated in an unusual reaction to quinaldic acid, a prominent urinary excretion product. 

Free amino acids are further catabolized into several volatile flavor compounds. However, the pathways involved are not fully known. A detailed summary of the various studies on the role of the catabolism of amino acids in cheese flavor development was published by Curtin and McSweeney (2004). Two major pathways have been suggested (1) aminotransferase or lyase activity and (2) deamination or decarboxylation. Aminotransferase activity results in the formation of a-ketoacids and glutamic acid. The a-ketoacids are further degraded to flavor compounds such as hydroxy acids, aldehydes, and carboxylic acids. a-Ketoacids from methionine, branched-chain amino acids (leucine, isoleucine, and valine), or aromatic amino acids (phenylalanine, tyrosine, and tryptophan) serve as the precursors to volatile flavor compounds (Yvon and Rijnen, 2001). Volatile sulfur compounds are primarily formed from methionine. Methanethiol, which at low concentrations, contributes to the characteristic flavor of Cheddar cheese, is formed from the catabolism of methionine (Curtin and McSweeney, 2004 Weimer et al., 1999). Furthermore, bacterial lyases also metabolize methionine to a-ketobutyrate, methanethiol, and ammonia (Tanaka et al., 1985). On catabolism by aminotransferase, aromatic amino acids yield volatile flavor compounds such as benzalde-hyde, phenylacetate, phenylethanol, phenyllactate, etc. Deamination reactions also result in a-ketoacids and ammonia, which add to the flavor of... 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

Catabolism of tryptophan can be divided into the serotonin and 3-hy-droxyanthranilic acid pathways, the latter being by far the more prevalent. It may lead to the formation of NAD+ or to a-ketoadipic acid. Only about 3% of 3-... 

Figure 20.21 Catabolism of tryptophan by the serotonin and 3-hydroxyanthranilate pathways. B, B2, and B6 indicate the participation of coenzymes derived from the respective vitamins. Notice that tryptophan is glucogenic and ketogenic, because it produces alanine on the one hand, and acetoacetyl-CoA on the other.

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

The catabolism of d- and of L-tryptophan in P. aureofaciens is different.67 Only the latter isomer is catabolized by the kynurenine pathway, and it also induces the enzymes of this pathway. Added L-tryptophan may then be catabolized by this pathway. That which is will not be available for biosynthesis of pyrrolnitrin. In support, a mutant that lacks the first enzyme of this catabolic pathway showed a 30-fold increase in the production of pyrrolnitrin as compared to normal organisms.67 D-Tryptophan, not suffering catabolism in this way, will be more readily available, through slow conversion into L-tryptophan, for biosynthesis of... 

In isolated hepatocytes, after maximum induction of tryptophan dioxygenase by glucocorticoids, the uptake of tryptophan into the cells has a control coefficient of 0.75, whereas the control coefficient of tryptophan dioxygenase falls to 0.25. Therefore, the induction of tryptophan dioxygenase has only a limited effect on tryptophan catabolism and NAD synthesis (Salter and Pogson, 1985 Salter et al., 1986). In isolated perfused liver, although cortisol leads to a several-fold increase in tryptophan dioxygenase activity, there is only a relatively small increase in the rate of clearance of tryptophan from the perfusion medium (Kim and Miller, 1969). 

Catabolism of tyrosine and tryptophan begins with oxygen-requiring steps. The tyrosine catabolic pathway, shown at the end of this chapter, results in the formation of fumaric acid and acetoaceticacid, Iryptophan catabolism commences with the reaction catalyzed by tryptophan-2,3-dioxygenase. This enzyme catalyzes conversion of the amino acid to N-formyl-kynurenine The enzyme requires iron and copper and thus is a metalloenzyme. The final products of the pathway are acetoacetyl-CoA, acetyl-Co A, formic add, four molecules of carbon dioxide, and two ammonium ions One of the intermediates of tryptophan catabolism, a-amino-P-carboxyrnuconic-6-semialdchydc, can be diverted from complete oxidation, and used for the synthesis of NAD (see Niacin in Chapter 9). 

Ammonium ions are produced by the catabolism of a number of amino acids. Glutamate dehydrogenase is the major source of ammonium ions in the body. Ammonium ions are also produced from the catabolic pathways of serine, histidine, tryptophan, glycine, glutamine, and asparagine. L-Amino acid oxidase and... 

As mentioned earlier, milk was often used to treat pellagra however, neither milk nor eggs contain very much niacin. The question arises How can milk reverse the symptoms of a disease known to result mainly from niacin deficiency The answer lies in a consideration of the pathway of catabolism of one of the amino acids, tryptophan. The breakdown of tryptophan may follow a number of different routes, including that shown in Figure 9.68. The final pniduct of this pathway is nicotinic acid ribonucleotide, which can be converted to NAD. A small fraction of... 

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