Hydroxylases aromatic ring

Deazaflavins with Monooxygenases Aromatic Ring Hydroxylases... 

Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) is difficult and rarely done in the laboratory., but occurs much more frequently in biological pathways. An example is the hydroxylation of p-hydroxyphenyl acetate to give 3,4-dihydroxyphenyl acetate. The reaction is catalyzed by p-hydroxyphenylacctate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH2. 

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

An intramolecular hydrogen migration observed in the hydroxylation of aromatic rings in certain enzyme-catalyzed reactions as well as some chemical reactions. The rearrangement was first observed at the National Institutes of Health (hence the name NIH ) in studies of the synthesis of L-tyrosine from L-phenylalanine via phenylalanine hydroxylase. Observation of this shift requires appropriate deuteration of the aromatic reactant. 

In addition to these classical aromatic ring hydroxylations, many nitrogen heterocycles are substrates for molybdenum-containing enzymes, such as xanthine oxidase and aldehyde oxidase, which are present in the hepatic cytosolic fractions from various animal species. The molybdenum hydroxylases (B-75MI10902) catalyze the oxidation of electron-deficient carbons in aromatic nitrogen heterocycles. The reactions catalyzed by these enzymes are generally represented by equations (2) and (3). 

Tyrosine hydroxylase uses BH4 to activate O,. One oxygen atom is attached to tyrosine s aromatic ring, while the other atom oxidizes the coenzyme. DOPA, the product of the reaction, is used in the synthesis of the other catecholamines. 

Tyrosine hydroxylase is an iron-containing mixed function oxidase that utilizes tetrahydrobiopterin, oxygen, and L-tyrosine as cosubstrates. Molecular oxygen is transferred from O2 to the aromatic ring of tyrosine. In recent years the molecular properties and the mechanisms that regulate the activity of this enzyme have been studied in depth by several laboratories (Kuhn and Lovenberg, 1983). 

As shown in Scheme 13.63, tabersonine, in the presence of tabersonine 16-hydroxylase (EC 1.14.13.73), is converted to 16-hydroxytabersonine. The reaction requires both NADPH and oxygen (O2), and NADP and water (H2O) are produced. Tabersonine 16-hydroxylase is a heme-thiolate protein (a P45o).The phenolic hydroxyl group on the aromatic ring undergoes methylation (tabersonine 16-O-methyltransferase, EC 2.1.1.94), while 5-adenosylmethionine is converted to... 

The hydroxylation of aromatic substrates by enzymes such as L-phenylalanine hydroxylase has been extensively studied in the National Institute of Health, Bethesda, USA, and it has been shown that the hydroxylation reaction is frequently accompanied by an intramolecular migration of the group or atom which is being displaced to an adjacent ortho position on the aromatic ring. This effect has been appropriately termed the NIH shift and detailed study of this type of reaction has led to some important conclusions regarding the precise nature of the chemical reactions involved in aromatic hydroxylation. In particular it has led to the suggestion that these enzymic reactions may proceed via arene... 

An important group of mixed function oxidases which occur in all types of organism and which are critical in the metabolism of the aromatic amino adds and other aromatic substrates are the aromatic hydroxylases. Their mode of action, the overall stoichiometry of which is represented in the sequence below, results in the introduction of a phenolic hydroxyl group in an aromatic ring system and has been the subject of intensive study. Pyridine and flavin nucleotides, cytochromes, metals (Fe, Cu), ascorbate and pteridine derivatives (H2X) may serve as electron donors. Most, but not all, of these en2yme reactions require transition metal ions for full activity. 

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