Phenylalanine biosynthetic pathway

Many biologically important routes of amino acid utilization, other than those leading to incorporation into proteins, are known. Some of these routes are distinctly anabolic pathways in which the amino acids serve as an initial substrate in an independent biosynthetic pathway. Other simple pathways involve the conversion of one amino acid to another, such as the formation of tyrosine from phenylalanine. The utilization of glycine in the formation of porphyrin derivatives occurs by very complex highly branched pathways. Some other biologically important pathways lead to the biosynthesis of small peptides as in the biosynthesis of glutathione. 

An alternative biosynthetic pathway towards SA was hypothesized to exist after experiments with labeled benzaldehyde, benzyl alcohol, and phenylalanine resulted in lower incorporation of the label in SA than... 

Figure 1.35 Schematic diagram of the phenolic biosynthetic pathway accompanied by the key enzymes involved. Enzyme abbreviations PAL, phenylalanine ammonia-lyase BA2H, benzoic acid 2-hydroxylase C4H, cinnamate 4-hydroxylase COMT-1, caffeic/5-hydroxyferulic acid O-methy I transferase 4CL, p-co um a ra te C o A ligase F5H, ferulate 5-hydroxylase GT, galloyltransferase ACoAC, acetylCoA carboxylase.

The biosynthetic pathway for salicylic acid is not clear. At present, at least two pathways have been proposed. Each branches from phenyl-propanoid biosynthesis after phenylalanine has been converted to trans-cinnamic acid by phenylalanine ammonium lyase (PAL). In one scheme (Pathway 1 Fig. 4), tram-cinnamic acid would be converted to 2-hydroxy cinnamic acid (or 2-coumaric acid) by a cinnamate 2-hydroxylase. This compound could then be converted to salicylic acid via -oxidation possibly through an acetyl coenzyme A (CoA) intermediate. Alternatively, tram-cinnamic acid could be oxidized to benzoic acid and then hydrox-ylated via a postulated o-hydroxylase activity. The details of this pathway, particularly in tobacco and cucumber, deserve further study. 

FIGURE 3.1 The biosynthetic pathway from chorismate to L-phenylalanine in Escherichia coli K12. The mnemonic of the genes involved are shown in parentheses below the enzymes responsible for each step. Compound 1 is L-phenylalanine, 2 is chorisimic acid, 3 is prephenic acid, and 4 is phenylpyruvic acid. 

Fig. 1. Simplified diagram of the phenylpropanoid and flavonoid biosynthetic pathways. Enzymes that catalyze the reactions are placed on the left-hand side, and transcription factors on the right-hand side of the arrows. Both transcription factors for which their control over the enzymatic steps has been genetically proven, as well as transcription factors that have been shown to interact with promoters of the structural genes, are shown. PAL Phenylalanine ammonia lyase C4H cinnamate 4-hydroxylase 4CL 4-coumaroyl-coenzyme A ligase CHS chalcone synthase CHI chalcone-flavanone isomerase F3H flavanone 3(3-hydroxylase DFR dihydroflavonol 4-reductase AS anthocyanin synthase UFGT UDP glucose-flavonol glucosyl transferase RT anthocyanin rhamnosyl transferase...

Scheme 4.12 Catalytic antibody 1F7 was raised against the transition state analog 28 and possesses modest chorismate mutase activity. It can complement a permissive yeast strain that is auxotrophic for phenylalanine and tyrosine by replacingthe natural enzyme (CM) in the shikimate biosynthetic pathway.

Attenuation of transcription is relatively common in bacterial gene expression and occurs in at least six other amino acid biosynthetic pathways (histidine, threonine, phenylalanine, leucine, isoleucine, and valine). These are also based on the coupling of transcription and translation. 

Phenylpropanoids have an aromatic ring with a three-carbon substituent. Caffeic acid (308) and eugenol (309) are known examples of this class of compounds. Phenylpropanoids are formed via the shikimic acid biosynthetic pathway via phenylalanine or tyrosine with cinnamic acid as an important intermediate. Phenylpropanoids are a diverse group of secondary plant compounds and include the flavonoids (plant-derived dyes), lignin, coumarins, and many small phenolic molecules. They are known to act as feeding deterrents, contributing bitter or astringent properties to plants such as lemons and tea. 

Alkaloids thus represent one of the largest groups of natural products, with over 10,000 known compounds at present, and they display an enormous variety of structures, which is due to the fact that several different precursors find their way into alkaloid skeletons, such as ornithine, lysine, phenylalanine, tyrosine, and tryptophan (38-40). In addition, part of the alkaloid molecule can be derived from other pathways, such as the terpenoid pathway, or from carbohydrates (38-40). Whereas the structure elucidation of alkaloids and the exploration of alkaloid biosynthetic pathways have always commanded much attention, there are relatively few experimental data on the ecological function of alkaloids. This is the more surprising since alkaloids are known for their toxic and pharmacological properties and many are potent pharmaceuticals. 

The low incorporation of phenylalanine precludes its involvement as an intermediate in the normal biosynthetic pathway to tyrosine and indicates that tyrosine and phenylalanine have different metabolic pathways in H. canadensis. 

Fuller details on the incorporation of phenyllactic acid (25) into tropane alkaloids have been published." This acid is a better precursor than phenylalanine for the acid fragments of (20), (21), and (22). The significance of this difference is doubtful it may be the result of several causes, the simplest being more effective diversion of phenylalanine into other biosynthetic pathways. None the less phenyllactic acid (25) is clearly a precursor for tropic acid (19) and atropic acid [as (22)] since it is specifically incorporated and moreover labels the alkaloids in the same way as phenylalanine does. 

Both alkaloids have (+) and (-) forms but only the (-) hyoscyamine and (-) scopolamine are active. The biosynthetic pathway of tropane alkaloids, Fig. (1) is not totally understood, especially at the enzymatic level. Edward Leete has pioneered the biosynthetic studies of tropane alkaloid since 1950"s using whole plants and isotope labels [85-86]. The tropane alkaloid hyoscyamine is bioconverted by the enzyme H6H (hyoscyamine 6p-hydroxylase, EC 1.14.11.11) to scopolamine via 6p-hydroxyhyoscyamine. Hyoscyamine is the ester of tropine and (S)-tropic acid. The (S)-tropic acid moiety derives from the amino acid L-phenylalanine, while the bicyclic tropane ring derives from L-omithine primarily or L-arginine via tropinone. Tropinone is stereospecifically reduced to form either, tropine which is incorporated into hyoscyamine, or on the other hand into pseudotropine which proceeds to calystegines, a group of nortropane derivates that were first found in the Convolvulaceae family [87]. 

Davis concluded that shikimic acid was a common precursor of phenylalanine, tyrosine, tryptophan, p-aminobenzoic acid, p-hydroxybenzoic acid, and an unknown sixth factor, and he next set out to determine other substances lying on the biosynthetic pathway. The various mutants were therefore tested for syntrophism, i.e., for the ability of one mutant to produce a substance necessary for the growth of another mutant. There was thus found a thermolabile substance, X, which was a true precursor of shikimic acid (184). X was isolated from culture filtrates and identified as 5-dehydroshikimic acid (744). Similar experiments revealed a substance, W, which was a true precursor of substance X (187, 193). This also was isolated and shown to be 5-dehydroquinic acid (906). The enzyme, named 5-dehydroquinase, converting dehydroquinic acid to dehydroshikimic acid has been partially purified (606). It is fairly stable, has a high specificity, appears to have no cofactors, and is of wide occurrence in bacteria, algae, yeasts, and plants but, as expected, could not be found in mammalian liver. 

A. The patient, despite being put on a low-Phe diet, exhibits neurologic problems resulting from an inability to synthesize catecholamine and indoleamine neurotransmitters. This is caused by a deficiency in dihydropteridine reductase (DHPR). DHPR regenerates tetrahydro-biopterin (BH ), which is oxidized to dihydrobiopterin by phenylalanine hydroxylase, as well as tyrosine hydroxylase and tryptophan hydroxylase (tryptophan 5-monooxygenase). If phenylalanine hydroxylase were deficient, a diet low in Phe would alleviate the effects. Since the urinary biopterin concentration is elevated, a deficiency in GTP cyclohydrolase I is eliminated because that is an enzyme in the biosynthetic pathway of BH. Phe hydroxylase, Tyr hydroxylase, and Tip hydroxylase activities are low because of a lack of BH. ... 

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