Tryptophan as precursor

FIGURE 18-22 Tryptophan as precursor. The aromatic rings of tryptophan give rise to nicotinate, indoleacetate, and serotonin. Colored atoms trace the source of the ring atoms in nicotinate. 

Thus, indole-3-acetic acid is biosynthesized both in higher plants and microorganisms via different pathways using the amino acid L-tryptophan as precursor. The same hormone is also obtained, for instance, by transformation of glucobrassicin, an indole glucosinolate widely distributed in Brassicaceae and related families (Eef.20). 

This is a very large group of alkaloids whose basic structure contains a pyrrole ring fused to a benzene ring. Biosynthesis of pure indoles involves the amino acid tryptophan as precursor, while that of a major subgroup of the indoles, including the Catharanthus and Rauwolfia alkaloids, involves a second precursor— the monoterpene iridoid loganin. 

Fig. 23.1 L-tryptophan as precursor for ergoline ring formation as a common scaffold of EAs...

In the course of their investigation of the enantioselective total synthesis of avarainvillamide and the stephacidins, the Baran group has developed a method for the dehydrogenation of tryptophan as well as a one-step tryptophan synthesis from pyroglutamate and substituted aniline precursors <06JACS8678>. 

Since tryptophan (and its decarboxylation product, tryptamine) serve as precursors in many synthetic and biosynthetic routes to /J-carbolincs, it is not surprising that C-1 of the /J-carbolinc ring is the most common site of substitution (as it is the only ring atom of the /J-carbolinc ring system not derived from tryptophan). Indeed, this is the only site of substitution for many /J-carboline natural products. Two examples of naturally occurring /J-carbolines substituted only at C-1 which possess antitumor activity are manzamine A and manzamine C (Fig. 2). Owing to its greater simplicity and nearly equal antitumor activity, most initial synthetic efforts were directed toward manzamine C [11,12]. 

The biosynthesis of tryptophan. Tryptophan is synthesized in five steps from chorismate. Each step requires a specific enzyme activity. The four intermediates between chorismate and tryptophan serve no function other than as precursors of tryptophan. The detailed steps of each reaction in this sequence are described in chapter 21. 

TCDD was investigated. No changes were found in epinephrine and dopamine in the hypothalamus or in dopamine and its metabolites in the striatum. However, tryptophan (a precursor of serotonin) levels in plasma and brain were increased and this was paralleled by increases in brain serotonin and 5-hydroxyindolacetic acid (the major serotonin metabolite) (Rozman et al. 1991). Based on the results of these experiments, Rozman et al. (1991) proposed that decreased PEPCK activity decreases gluconeogenesis and leads to increased plasma concentrations of glycogenic amino acids, such as tryptophan. Increased tryptophan leads to increase in serotonin release in the brain and to appetite... 

The worldwide amino acids market amounts to about 5 billion. MSG and the animal feed additives, methionine and lysine, account for about 75 percent of this sales value. The other amino acids are used as precursors in pharmaceuticals, food additives, and animal feed. The worldwide demand for glutamic acid is about 800,000 tons/year, 300,000 tons/year for methionine, and 500,000 tons/year for lysine. Other significant amino acids such as aspartic acid, phenylalanine, threonine, and glycine, each have a worldwide market of about 10,000-20,000 tons/ year. Tryptophan and cysteine command a global market in the thousands of tons as well. 

Pseudoakuammicine is the first racemic base to be discovered in the strychnine-yohimbine series of alkaloids, and the question of its origin naturally arises. The only stage in the extraction of Picralima seeds during which racemization of akuammicine might have occurred involved prolonged percolation with hot methanol however, as already discussed, akuammicine is not racemized under these conditions but suffers a more extensive decomposition. In any event, such a racemization would necessarily involve fission of the 3,7 and 15,16 bonds, followed by a nonspecific resynthesis, which is considered to be a very unlikely possibility. It was therefore suggested that, in the plant, pseudoakuammicine is produced by a nonspecific biosynthesis this would accord with its formation from a tryptophan-phenylalanine precursor, but not from an optically pure prephenic acid derivative (40). 

A number of studies have investigated the equivalence of dietary tryptophan and preformed niacin as precursors of the nicotinamide nucleotides, generally by determining the excretion of -methyl nicotinamide and methyl pyridone carboxamide in response to test doses of the precursors, in subjects maintained on deficient diets. 

It is thus apparent that the utilization of tryptophan as a precursor for NAD synthesis depends on both the amount of tryptophan to be metabolized and also the rate of metabolic flux through the pathway. The activities of three... 

Bender DA and Olufunwa R (1988) Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells. British Journal of Nutrition 59, 279-87. 

Oduho GW, Han Y, and Baker DH (1994) Iron deficiency reduces the efficacy of tryptophan as a niacin precursor. Journal of Nutrition 124,444-50. 

Tryptophan (fig. 8) is one of the twenty amino acids used by all of life on Earth to build proteins. Although plants, fungi, bacteria, and some other organisms can biosynthesize tryptophan from smaller carbon molecules, humans cannot and must ingest tryptophan as part of their diet. That is, tryptophan is one of the essential amino acids. In fungi and plants, tryptophan is the chemical precursor for the biosynthesis of tryptamines such as DMT and psilocybin. In humans and other animals, tryptophan is the precursor for the synthesis of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT fig. 9). 

The finding that tryptophan-2-i4C (CII) may also serve as a precursor for tropic acid 94) labeled in the carboxyl group (XXIIId) seemed to be contradictory. However, it was interpreted later 93) by assuming tryptophan as a source for C02, which becomes incorporated into phenylpyruvic acid this acid is supposed to be formed from phenylalanine. However, this is an explanation but not a rigorous proof. 

Bender DA, Magboul BI, Wynick D. 1982. Probable mechanisms of regulation of utilization of dietary tryptophan, nicotinamide and nicotinic acid as precursors of nicotinamide nucleotides in the rat. Br. J. Nutr. 48 119-27... 

Neurotransmitters and NREM Sleep in Humans. Several agents that influence the brain levels of neurotransmitters have a profound effect on NREM sleep in humans. Most studies indicate that tryptophan, a precursor of serotonin, increases NREM sleep time and decreases sleep latency (38, 39). Tryptophan was used one time as a sleep-inducing agent, but it is no longer available because it causes eosinophilic myalgia syndrome. 

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