The aromatic nucleus

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1.1 Aromatization of 6-membered carbon and heterocyclic rings.

Prephenate dehydrogenase (E C.

Prephenate 0 ^-hydroxyphenylpyruvate

The amino acid composition of A. aerogenes enzyme, molecular weight 76 000, has been determined; it is involved in the biosynthesis of tyrosine [K873].

Prephenate dehydrogenase (NADP+)

The mung bean (Vigna radiata) enzyme, molecular weight 52 000, requires NADPH; it may be identical with pretyrosine dehydrogenase [B290]

Prephenate dehydratase (E.C.

Salmonella typhimurium enzyme, optimum pH 8.5, is part of a complex with chorismate mutase (E.C. The reaction product, phenylpyruvate, is further converted into phenylalanine [K859].

Arogenate (pretyrosine) dehydrogenase

Vigna radiata (mung bean) enzyme, molecular weight 52 000, may be identical with prephenate dehydrogenase [B290].

Nicotiana silvestris enzyme is inhibited by l-tyrosine and substituted tyrosines [C501].

Corynebacterium glutamicum and Brevibacterium flavum enzymes have molecular weights of 158 000, and B. ammoniagenes 68 000. They are not inhibited by tyrosine, and p -chloromercuribenzoate inhibition is reversed by thiols. Contrary to some earlier reports, these organisms lack the p -hydroxyphenylpyruvate pathway for the formation of tyrosine [B47].

Actinoplanes missouriensis enzyme, molecular weight 68 000, has an optimum at pH 9.5 [F277].

Streptomyces phaeochromogenes enzyme is a dimer with subunit molecular weight 28 100 and pI 4.45 [D880].

This reaction has also been observed in Microtetraspora glauca [F222], Claviceps [E234], Streptomycetes [C695] and Flavobacterium devorans [C115].

Phenylalanine formation from arogenate

This reaction has been detected in Claviceps [E234].

Anthranilate synthase; (E.C.

Chorismate + glutamine or NH3 0 anthranilate

Saccharomyces cerevisiae enzyme is dimeric, molecular weight 130000, and subunit molecular weight 64000 [D512]. Enterobacter liquefaciens and Erwinia carotavora enzymes have molecular weights of 140 000, and Aeromonas formicans p-Aminobenzoate formation from chorismate

220 000 [A1481]. Claviceps enzyme has an optimum pH of 7.8 or 8.6 using glutamine as co-substrate. It requires Mg2 + , partly replaceable by Mn2+ or Co2 + , is stimulated by K + , Na + or NH+ and is inhibited by tryptophan, chanoclavine, elymoclavine, indoleacrylate and prephenate [A2552].

Shikimate forms phenazine-1-carboxylate in Pseudomonas aureofaciens [A958]; earlier publications suggest that the pathway is via chorismate and anthranilate.

p -Aminobenzoate formation from chorismate

Streptomyces coelicolor catalyzes this reaction, but isochorismate is not a substrate; however, both compounds are precursors of p-aminobenzoate in S. aminophilus and Enterobacter aerogenes; isochorismate may initially be converted into chorismate [F111]. S. griseus enzyme, molecular weight 50 000 uses ammonia or glutamine as the source of the amino group [D734].

p-Aminophenylalanine formation from chorismate

In Streptomyces this reaction is an initial step in the formation of chloamphenicol. Its formation is considered to be a four-stage biosynthesis including a transamination, and the reaction is stimulated by an aminotransferase from the crude extract, as well as by several other enzymes present [A2461, B158].

Benzoate formation from shikimate

This reaction has been observed in rat [A2706].

p -Hydroxybenzoate formation from shikimate

This reaction occurs in Lithospermum erythrorhizon as an early step in the formation of the naphthoquinone shikonin and y-glutaminyl-4-hydroxybenzene [A3763, B810].

Phenylalanine formation from shikimate

Phenylalanine and tyrosine are formed from shikimate in Reseda lutea, R. odorata and Iris. Previous publications indicate an involvement of prephenate [A1601].

3-Carboxyphenylalanines formed from shikimate

3-Carboxyphenylalanine and 3-carboxytyrosine are formed from shikimate in Reseda lutea, R. odorata and Iris, as well as phenylalanine and tyrosine. The carboxyl group arises from shikimate; it is not considered that carboxylation of the parent amino acid is involved [A1601].

Phenazine-1-carboxylate and iodinin formation from shikimate

These reactions involve the formation of a phenazine ring system, apparently incorporating two shikimate molecules, probably with anthranilate as an early intermediate.

The formation of phenazine-1-carboxylate has been observed in Pseudomonas aureofaciens [A958].

The formation of iodinin has been observed in Brevibacterium/Chromobacterium iodinum [A958, A2941].

Menaquinone MK-9(II-H2) formation from shikimate

This reaction, which involves the formation of a naphthoquinone, has been observed in Mycobacterium phlei [A691].

Catechol formation from shikimate and dehydroshikimate

The first reaction has been observed in rat, [A2706] and the second in E. coli, where it is a major pathway for the anaerobic utilization of glucose [G366].

o-Succinylbenzoate formation from isochorismate o -Succinylbenzoate formation from isochorismate

E. coli and Aerobacter aerogenes enzymes catalyze this reaction, with a-oxoglutarate as co-substrate. It appears that earlier claims that chorismate is the substrate were incorrect. The enzyme, optimum pH 8.3, requires thiamine pyrophosphate as coenzyme, and it may be a Mn2 +-containing enzyme [D682, E430, E457]. The reaction product is the starting point for the formation of a range of substituted naphthalene natural products.

3-Amino-5-hydroxybenzoate formation from 5-deoxy-5-amino-3-dehydroshikimate

This reaction has been detected in Amycolatopsis mediterranei. The enzyme, which contains bound pyridoxal phosphate, catalyzes both an a,b-dehydration and a stereospecific 1,4-enolisation during the reaction sequence. The product is a key intermediate in the formation of rifamycin [J643].

cis -Dihydrobenzene-1,2-diol dehydrogenase;

cis-1,2-Dihydroxycyclohexa-3,5-diene 0 catechol

Mouse kidney contains four soluble (three minor) isozymes. Two minor ones are immunologically identical with aldehyde reductase (E.C. 1.2.1 class) and 3a-hydroxysteroid dehydrogenase (E.C. The other two, molecular weight 39 000, require NAD(P)+ as coenzyme. Both cis and irons isomers are substrates, as well as other dihydrodiols; p -nitrobenzaldehyde and quinones are also reduced [F377].

An enzyme in Bacterium acts only on cis-isomers [B871]. Pseudomonas putida enzyme, a homotetramer, molecular weight 102000, acts on a range of aromatic hydrocarbon cis- dihydrodiols except those substituted on K-regions [A1298, A1591].

Pseudomonas putida cis-naphthalene-1,2-dihydrodiol dehydrogenase (E.C. and cis-biphenyl-2,3-dihydrodiol dehydrogenase both oxidize cis-naphthalene-1,2-dihydrodiol and cis-biphenyl-2,3-dihydrodiol as well as cis-2,2',5,5'-tetrachlorobiphenyl-3,4-dihydrodiol. They both require NAD+ [K196].

Pseudomonas cis- chlorobenzene dihydrodiol dehydrogenase acts on cis-(1R ,2S)-indan-1,2-diol, but not on cis-(1S,2R )-indan-1,2-diol. Some enantiomeric selectivity is observed with p -halotoluene-2,3-dihydrodiols, cis-1,2-dihydroxytetralin and cis -naphthalene-1,2-dihydrodiol [K348].

Xanthobacter flavus enzyme is a homotetramer, monomeric molecular weight 26 500 and pI 5.4. It requires NADP+ (NAD+ is less effective) and acts on cis-3,6-dichlorobenzene-1,2-dihydrodiol and benzene-1,2-dihydrodiol [J186].

Bacillus enzyme is a homohexamer, monomeric molecular weight 29 500, pI 6.4 and optimum pH 9.8. It oxidizes cis-toluene-2,3-dihydrodiol, and is stable up to 80° [E368].

trans -Dihydrobenzene-1,2-diol dehydrogenase;

trans-1,2-Dihydroxycyclohexa-3,5-diene 0 catechol

This and similar enzymes aromatize irons-dihydrodiols formed from benzene and a range of analogues formed from polynuclear hydrocarbons, including those that are carcinogenic. This reaction is one step in the potential degradation of these hydrocarbons; the catechols so formed could undergo ring fission, at least in microorganisms.

An enzyme in pig lens oxidizes this and other similar substrates, utilising NADP+. Quinones and nitrobenzaldehydes are also substrates for the reverse reaction [F389].

Monkey liver cytosol contains four isozymes, molecular weights in the range 36000-39000, each with a similar range of specificities, and optima at pH 5.8, 6.2, 7.9 and 8.7. One isozyme was formerly known as indanol dehydrogenase (E.C. [F388]. One at least is a dimer that is inactive towards cis - isomers [F391].

1,6-Dihydroxycyclohexa-2,4-diene-1-carboxylate dehydrogenase

Hamster liver cytosol contains five isozymes with a broad specificity, molecular weight about 35000 [F153].

Guinea pig liver contains four major and four minor isozymes, molecular weights about 34 000, except for two minor ones, molecular weights 26 500 and 14500. The specificity is broad [E67].

Rat liver cytosolic enzyme requires NADP as co-substrate, and acts on trans-naphthalene-1,2-dihydrodiol and trans-benzpyrene-7,8-dihydrodiol [E583].

Mouse liver enzyme has been separated into four isozymes that require NADP. Two are monomers, molecular weights 30 000 and 34 000, and two dimers, molecular weights 64 000 and 65000, pI 8.1, 6.2, 5.5 and 5.4, respectively [C712]. Another study found two cytosolic forms that were identified as 17b-hydroxysteroid dehydrogenase (major; E.C. and and aldehyde reductase. The major one also oxidizes a range of alcohols and reduces a range of aldehydes and ketones [E821].

Beef liver cytosolic enzyme contains three enzymes that are active towards trans-benzene dihydrodiol. One is 3a-hydroxysteroid dehydrogenase and a second is a high Km aldehyde reductase. The third also acts on other dihydrodiols including trans-naphthalene dihydrodiol; it is a distinctly different activity [G750].

1,6-Dihydroxycyclohexa-2,4-diene-1-carboxylate dehydrogenase (E.C.

2,3-Dihydro-2,3-dihydroxybenzoate dehydrogenase; (E.C.

Aerobacter aerogenes and E. coli enzymes require NAD + as co-substrate [K876].

o -Succinylbenzoate synthase

Amycolaptosis enzyme acts on 2-hydroxy-6-succcinyl-2,5-cyclohexadienecarboxylate as substrate [K68].

Kynurenate-7.8-dihydrodiol dehydrogenase

Pseudomonas fluorescens enzyme requires NAD+ for the formation of 7,8-dihydroxykynurenate [K874].

trans -Acenaphthene-1,2-dihydrodiol dehydrogenase (E.C.

Rat liver cytosolic enzyme acts on the ( ), but not on the ( ) isomer (an inhibitor), with NADP+ as co-substrate, whereas NAD + is inactive. A further substrate is (—)-1-phenylethanol. Activity is also found in mouse, guinea pig, rabbit, hamster, dog, cat and pig liver. Some of these can accept NAD+ as co-substrate; it has been suggested that more than one enzyme may be involved [K817].

Alcaligenes eutropus enzyme, molecular weight 95000 and optimum pH 8.0 may be a homotetramer. It forms catechol and CO2, and requires NAD +; NADP + is ineffective, and no other cofactors are required [K944].

cis -1,2-dihydroxycyclohexa-3,5-diene-1-carboxylate dehydrogenase (E.C.

Pseudomonas putida and Acinetobacter calcoaceticus enzymes, molecular weight 28 000 form catechol from the substrate [K763].

Aromatization of dihydropyridines

Nilvadipine, a 1,4-dihydro-4-phenylpyridine is aromatized in rat liver microsomes, and utilises NADPH. The reaction is inhibited by P450 inhibitors [E847]. Many metabolic studies on calcium channel blockers with similar structures to nilvadipine have demonstrated that a major proportion of each drug is similarly aromatized.

A large number of studies with the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine (MPTP), which causes a drug-induced parkin-sonism, have demonstrated that the proximal

Tetrahydroprotoberberine aromatization toxin is 1-methyl-4-phenylpyridinium (MPP + ). Metabolic studies have detected the formation of MPP+ in mouse, monkey, rat, man and beef (e.g. [E3, D222, D141, E3, F458] respectively). The formation of 2,3-dihydro-1-methyl-4-phenylpyridinium has also been observed, and this in turn is converted into MPP+, at least in mouse [E684]. A major study with human placental MAOA and beef liver MAOB found that a large range of MPTP analogues, particularly those with substituents on the aryl moiety are substrates. Although the products were not identified, it was assumed that they were MPP + analogues [F395].

Tetrahydroprotoberberine aromatization

Berberis wilsonae enzyme is a flavoprotein, molecular weight 100000 and optimum pH 8.9. Tetrahydroprotoberberine yields protoberberine, presumably via the 7,14-dehydroberbinium analogue; canadine and tetrahydrojatrorrhizine are also substrates. The reaction requires oxygen and forms peroxide as the second product. The enzyme is specific for (S)- isomers [D145].

Corydalis cava bulb protoberberine reductase, optimum pH 7.5, requires NADH for the reduction of protoberberines to (14R)-tetrahydroberberines, apparently in two stages. For instance, both berberine and 7,8-dihydroberberine are reduced to canadine. The reaction, which dearomatizes the heterocyclic ring, is reversible; both 7,8-dihydroberberine and (R)-canadine are oxidized to berberine, with NADP+ as coenzyme. Palmatine, dehydrosinactine, coptisine, columbamine, jatrorrhizine and dehydroscoulerine are also substrates [G136].

Tetrahydroberberine (canadine) aromatization

Thalictrum minus tetrahydroberberine oxidase is composed of 3 isozymes, two of which are specific. All have an optimum at pH 9.0. The molecular weight of one of the specific enzymes is more than 200 000, and the other, a trimmer, is 145 000 [H401].

Coptis japonica (S)-tetrahydroberberine oxidase (E.C. is a dimmer, molecular weight 58 000, and requires oxygen and Fe; it is highly specific. It aromatizes one of the hetero-cyclic rings [E678, E732].

Berberis aggregata aromatizes tetrahydroberberine, tetrahydrocolumbamine and tetrahydropalmatine, with the formation of a quaternary amino moiety [K947].

Aromatization of dihydromacarpine

Eschscholtzia californica enzyme, molecular weight 56 000, pI 8.8 and optimum pH 7.0, requires oxygen to oxidize dihydromacarpine to macarpine. This completes the aromatization of the ring system, including the formation of a quaternary nitrogen [E604].

Dihydrobcn/ophenanthridinc oxidase

Sanguinaria canadensis enzyme is composed of three isozymes, molecular weights 77 000, 67 000 and 59000 and optimum pH 7.0. It converts dihydrosanguinarine into sanguinarine and dihydrochelerythrine into chelerythrine, aromatizing the heterocyclic ring [G723]. Eschscholtzia californica enzyme, molecular weight 56 000, pI 8.8 and optimum pH 7.0, requires oxygen to convert dihydromacarpine into macarpine [E604]. In all of these a quaternary base is formed.

Many plant alkaloids contain an aromatic heterocyclic ring moiety. There may be an aromatizing step similar to this one, but in most cases the enzymology has not been studied.

D-Dopachrome tautomerase

Human enzyme is found in erythrocytes and other blood cells, but not in plasma, with 5,6-dihydroxyindole as the product [H872].

The enzyme that enolizes indole-3-pyruvate and p -hydroxyphenylpyruvate converts

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