Indolepyruvic acid

Numerous examples of modiflcations to the fundamental cyclodextrin structure have appeared in the literature.The aim of much of this work has been to improve the catalytic properties of the cyclodextrins, and thus to develop so-called artificial enzymes. Cyclodextrins themselves have long been known to be capable of catalyzing such reactions as ester hydrolysis by interaction of the guest with the secondary hydroxyl groups around the rim of the cyclodextrin cavity. The replacement, by synthetic methods, of the hydroxyl groups with other functional groups has been shown, however, to improve remarkably the number of reactions capable of catalysis by the cyclodextrins. For example, Breslow and CO workersreported the attachment of the pyridoxamine-pyridoxal coenzyme group to beta cyclodextrin, and thus found a two hundred-fold acceleration of the conversion of indolepyruvic acid into tryptophan. 

The analogues of serine and tyrosine were prepared from suitably protected hydroxy aldehydes and the tryptophan analogue from indolepyruvic acid. A wide selection of other o -aminophosphonous acids was also prepared from aliphatic, aromatic and heterocyclic aldehydes and aliphatic ketones. 

Thus we designed and synthesized a bicyclic pyridoxamine derivative carrying an oriented catalytic side arm (16) [11], Rates for conversion of the ketimine Schiff base into the aldimine, formed with 26 (below) and a-ketovaleric acid, indolepyruvic acid, or pyruvic acid, were enhanced 20-30 times relative to those carried out in the presence of the corresponding pyridoxamine derivatives without the catalytic side arm. With a-ketovaleric acid, 16 underwent transamination to afford D-norvaline with 90% ee. The formation of tryptophan and alanine from indolepyruvic acid and pyruvic acid, respectively, showed a similar preference. A control compound (17), with a propylthio group at the same stereochemical position as the aminothiol side arm in 16, produced a 1.5 1 excess of L-norvaline, in contrast to the large preference for D-amino acids with 16. Therefore, extremely preferential protonation seems to take place on the si face when the catalytic side arm is present as in 16. 

Tryptophan Indolepyruvic acid Serotoninb Serotonin is a neurotransmitter... 

D-Amino acids vary in availability with the species. For example d-phenylalanine is used by rat, mouse, and man (15, 35, 727, 730, 962), whereas D-tryptophan is used by the rat (53, 54, 759, 895), is partially used by the mouse and pig (139, 867), and is not used by man (7, 29). The utilization of the D-amino acids is probably determined by the relative rates of absorption of the D-amino acid from the intestine, and of conversion of d- to L-amino acid in the liver (288). The conversion of d- to L-phenylalanine is reduced in vitamin-Be deficiency (52), as is to be expected for a transformation involving transamination to phenylpyruvic acid. Phenylpyruvic and indolepyruvic acids, the a-keto acids corresponding to phenylalanine and tryptophan, may also, to an extent varying with the species, satisfy growTh requirements (e.g., 55, 109, 436, 725, 911). 

Anthranilic acid and indole are precursors of tryptophan in numerous microorganisms and fungi (e.g., 5, 263, 264, 602, 741, 783, 785, 816, 854, 855, 876), and it is probable that anthranilic acid is derived, with intermediate steps, from the common precursor, CP of diagram 1. The conversion of anthranilic acid to indole and tryptophan has been shown unambiguously in Neurospora with the use of isotopic techniques (93, 663). There may, however, be other pathways for tryptophan biosynthesis (45, 702). Tryptophan can, for example, be formed by transamination of indolepyruvic acid (e.g., 470, 912), which might be formed other than via anthranilic acid. Thus aromatic-requiring mutants have been found which accumulate unidentified indole compounds (307). 

Tryptophan can be converted to indolepyruvic acid either by oxidative deamination or by transamination (e.g., 739, 912) and the indolepyruvic acid can give rise to indoleacetic acid. The fate of indoleacetic acid formed by the bacterial flora of the mammalian gut is discussed below. Bacterial indolelactic acid (e.g., 757) is presumably derived from indolepyruvic acid, but indolelactic acid excreted by mammals (e.g. 17) may be of true mammalian rather than bacterial origin. Indolepropionic acid can also be formed by bacteria (e.g., 412, 633), but further metabolism in mammals of any indolepropionic acid formed in the gut is still obscure (904). Skatole (3-methylindole) has long been known as a product of bacterial decomposition of protein and is formed from tryptophan not only by the bacterial flora of the gut but also in putrefying secretions, e.g., sputum (756). It may well arise by decarboxylation of indoleacetic acid. 

There is evidence that both these routes can occur. The enzymes converting tryptophan to indoleacetic acid can be obtained in maize embryo juice the tryptophan is thought to arise from the endosperm (964). Indolepyruvic acid is also present in maize endosperm (837, 838), suggesting it to be an intermediate. On the other hand, tryptamine is converted to indoleacetic acid in plants (304, 815) and the amine oxidase responsible has been studied by Kenten and Mann (464). Consideration of the biogenesis of alkaloids, discussed later, suggests that both tryptamine and indoleacetaldehyde are likely to occur in plants. 

Squadrito et al.141 reported that indolepyruvic acid, a keto analog of tryptophan, at 100 mg per kg per day orally for 10 days, significantly decreased systolic blood pressure in three rat models (spontaneously hypertensive, DOCA + salt hypertensive, and Grollman hypertensive) but had no effect in normotensive rats. Such treatment caused enhanced levels of tryptophan in the cortex and diencephalon and enhanced brainstem serotonin content. Their results suggested that indolepyruvic acid lowered blood pressure in different rat models of hypertension, and the effect seemed to be correlated with an increase in cerebral serotonin metabolism. 

A modified cyclodextrin (25), which contains a pyridoxamine moiety, catalyzes the transamination as shown in Scheme 8 [39]. The reaction between (25) and indolepyruvic acid (26) is 200 times faster than the reaction between pyridoxamine and (26), since the first reaction is an intracomplex one and the second is an intermolecular one. Transamination is completed by the reaction of (27), formed by the reaction between (25) and (26), with another amino acid, regenerating (25). Thus... 

In our first study we attached a pyridoxamine unit to a primary carbon of jS-cyclodextrin (structure 12). We saw that pyridoxamine alone is able to transaminate pyruvic acid to form alanine, phenylpyruvic acid to form phenylalanine, and indolepyruvic acid to form tryptophan, all with equal reactivity by competition experiments. However, when the cyclodextrin was attached to the pyridoxamine there was a 200-fold preference for the indolepyruvate over pyruvate in one-to-one competition, forming greater than 98% of tryptophan, and in the competition with phenylpynivate and pyruvate the phenyManine was formed in greater than 98% as well. Thus the ability of the substrates to bind into the cyclodextrin cavity led to striking selectivities. In addition there was some chiral induction in these processes, since )3-cyclodextrin is itself chiral, but the magnitudes of the induction were quite modest. 

As phenolic compounds have been shown to interfere in indole biosynthesis CEef. 3)i the reciprocal, situation, i.e. inhibition of phenolic s thesis by indole compounds (mainly lAA, see belowj, weis considered to occur possibly at the level of PAL. The intermediate products of lAA synthesis, anthranilicoand indolepyruvic acids had a peculiar effect on the HOH formation from the radioactive phenylalanine by first completely repressing the formation and then, after a lag phaae of ca. 90 min, allowing it to proceed at the rate of the control. The common precursor of the aromatic amino acid shikimic acid showed, however, no effect, while the aromatic amino-acids tyrosine and tryptophan caused inhibition. 

Peptides Glutathione (D 23) Coenzyme, e.g., of glyoxalase, formaldehyde dehydrogenase, indolepyruvic acid-ketoenol-tautonierase and maleyl-acetoacetic acid isomerase... 

Breslow etal. made attempts to imitate the enzymatic transamination of vitamin B6, based on a j8-CD linked pyridoxamine 95 (Figure 37a). The transamination with the artificial enzyme for indolepyruvic acid 96 as substrate was 200 times faster than with pyruvic acid. However, a general problem of such enzyme mimics based on rather small molecules is the microenvironment. Enzymes are macromolecules and are able to fold in a specific manner to provide an active side that is robust and versatile through a combination of hydrophobic effects and specific substrate interactions like hydrogen bonds or salt bridges. In such a specific microenvironment, it is also possible to create regions in which a catalyzed reaction occurs in... 

Auxin Formation. Oxidation or transamination leads to the formation of indolepyruvic acid. Decarboxylation of the keto acid is presumed to result in the formation of indoleacetaldehyde, which can be oxidized by an aldehyde oxidase to indoleacetic acid (V). This compound is excreted by humans, but appears to be the natural auxin, a plant growth hormone. Degradation of auxin by plants appears to involve a peroxidase acting as an oxidase. Horseradish peroxidase plus Mn++ carry out the same... 

The correct structure was established by Homer. Kynurenic acid is formed from L-tryptophan and from indolepyruvic acid, but not from the D-amino acid. ... 

Indolmycin (7.66), diStreptomycesgriseus metabolite, is derived as shown in Scheme 7.7 [36]. Of particular interest is the C-methylation at what is C-3 in tryptophan (7.25). Mechanistically indolepyruvic acid [7.63) is an... 

In our first example (Fig. 1.13), the first in which a coenzyme was linked to a cyclodextrin, we synthesized compound 25, with a pyridoxamine covalently linked to a C-6 of /3-cyclodextrin. We saw transaminations of pyruvic acid, of phenylpyruvic acid, and of indolepyruvic acid to form alanine, phenylalanine, and tryptophan, respectively, and with high selectivity for the hydrophobic phenyl and indole derivatives relative to simple pyruvic acid. Relative to its reaction with simple pyridoxamine in solution, without an attached or unattached cyclodextrin, the indolepyruvate reacted 50 times faster with compound 25. Also, we saw a 5 1 preference for the formation of the L-phenylalanine relative to the d enantiomer in transamination by compoimd 25. ... 

In compound 25 we had attached the pyridoxamine to the primary C-6 position of the cyclodextrin, but in an earlier study we had seen that there were sometimes, but not always, advantages to attaching catalytic groups to the secondary face of a cyclodextrin. Thus we attached pyridoxamine to the secondary face of jS-cyclodextrin, and saw again a preference for the transamination of indolepyruvic acid and of phenylpyruvic add, but the preferences were only approximately half as large as those with compound 25. Thus here the original attachment of the cofactor to the primary face of the cyclodextrin was actually the best. 

In a second approach, we used the polymer with its attached hydrophobic chains, but had the pyridoxamine unattached, but carrying hydrophobic side chains itself. Thus in water the coenzyme bound into the hydrophobic core of the polymer, and so did the indolepyruvic acid. The acceleration in the synthesis of tryptophan by this system was 725,000-fold, relative to the rate with free pyridoxamine alone. 

Role of Riboflavin. Riboflavin deficiency has been found to produce abnormaUties in the metabolism of tryptophan (307-311). The deficiency leads to an increased excretion in the urine of kynurenine, anthranilic acid, and kynurenic acid and its conjugates (308, 309). In liver and kidney slices riboflavin deficiency leads to a decrease in indolepyruvic acid accumulation and an increase in the production of kynurenic acid and anthranilic acid from L-kynurenine (310, 311). The deficiency was also found to... 

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