Indolepyruvate

Oxidation, of Grignard reagents with peresters, 41, 91 43, 55 of 2-hydroxy-3-methylbenzoic acid to 2-hydroxyisophthalic acid by lead dioxide, 40, 48 of indene, 41, 53 44, 63 of indolepyruvic add, 44, 66 of methyl disulfide to methanesul finy 1 chloride by chlorine, 40, 62 of 2-exo-norbomyl formate by chromic add, 42, 79... 

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. 

Methyltransferases that utilize S-adenosyl-L-methionine as the methyl donor (and thus generating S-adenosyl-L-homocysteine) catalyze (a) A-methylation (e.g., norepinephrine methyltransferase, histamine methyltransferase, glycine methyltransferase, and DNA-(adenine-A ) methyltransferase), (b) O-methylation (e.g., acetylsero-tonin methyltransferase, catechol methyltransferase, and tRNA-(guanosine-0 ) methyltransferase), (c) S-methyl-ation (e.g., thiopurine methyltransferase and methionine S-methyltransferase), (d) C-methylation (eg., DNA-(cy-tosine-5) methyltransferase and indolepyruvate methyltransferase), and even (e) Co(II)-methylation during the course of the reaction catalyzed by methionine syn-thase. ... 

Most known thiamin diphosphate-dependent reactions (Table 14-2) can be derived from the five halfreactions, a through e, shown in Fig. 14-3. Each halfreaction is an a cleavage which leads to a thiamin- bound enamine (center, Fig. 14-3) The decarboxylation of an a-oxo acid to an aldehyde is represented by step b followed by a in reverse. The most studied enzyme catalyzing a reaction of this type is yeast pyruvate decarboxylase, an enzyme essential to alcoholic fermentation (Fig. 10-3). There are two 250-kDa isoenzyme forms, one an a4 tetramer and one with an ( P)2 quaternary structure. The isolation of ohydroxyethylthiamin diphosphate from reaction mixtures of this enzyme with pyruvate52 provided important verification of the mechanisms of Eqs. 14-14,14-15. Other decarboxylases produce aldehydes in specialized metabolic pathways indolepyruvate decarboxylase126 in the biosynthesis of the plant hormone indoIe-3-acetate and ben-zoylformate decarboxylase in the mandelate pathway of bacterial metabolism (Chapter 25).1243/127... 

Pyruvate dehydrogenase (Lipoyl, FAD, NAD+) multienzyme complex Pyruvate ferredoxin oxidoreductase Indolepyruvate ferredoxin oxidoreductase... 

Tire enzyme does not require lipoic acid. It seems likely that a thiamin-bound enamine is oxidized by an iron-sulfide center in the oxidoreductase to 2-acetyl-thiamin which then reacts with CoA. A free radical intermediate has been detected318 321 and the proposed sequence for oxidation of the enamine intermediate is that in Eq. 15-34 but with the Fe-S center as the electron acceptor. Like pyruvate oxidase, this enzyme transfers the acetyl group from acetylthiamin to coenzyme A. Cleavage of the resulting acetyl-CoA is used to generate ATR An indolepyruvate ferredoxin oxidoreductase has similar properties 322... 

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... 

INDOLMYCIN (20) is formed from pyruvate, and two enzymes active in initial stages of Its biosynthesis have been studied. They are a transaminase and aC-methyltransferase. The hypothetical route to indolmycin is by indole pyruvate, 3-methyl-indolepyruvate, indolmycenic acid (reduced alpha oxo group) and finally indolmycin which probably takes its amidine group from an arginine molecule 79. The closely related [pyrrolo (1,4) benzodiazepines] 80>81,82 antitumor antibiotics, anthramycin, tomaymycin and sibiromycin are formed from tryptophan (via the kynurenine pathway ), tyrosine and methionine-derived methyl groups 80.si.sz. 

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. 

Schutz, a., Golbik, R., Konig, S., Hubner, G., Tittmann, K. (2005), Intermediate and transition states in thiamin diphosphate-dependent decarboxylases. A kinetic and NMR study on wild-type indolepyruvate decarboxylase and variants using indolepyruvate, benzoylformate, and pyruvate as substrates. Biochemistry 44, 6164-6179. 

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. 

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