Oxygenase aromatic hydroxylation

Cytochrome P-450. Cytochrome P-450 enzymes consist of a large number of haem-containing mono-oxygenases which catalyze aliphatic and aromatic hydroxylations, epoxidations, as well as other oxidation reactions thus, these enzymes are able to cleave aromatic C-H bonds and also... 

Figure 2.24 Reactions catalysed by mono-oxygenases, hydroxylation of carbon centres, aromatic hydroxylation, epoxidation of alkenes, heteroatom oxidation and Baeyer-Villiger oxidation of a ketone.

A general review on oxygenase-catalyzed hydroxylation of aromatic compounds has appeared, which discusses this area in greater detail. ... 

The pterin-dependent oxygenases, typified by the aryl amino acid hydroxylases, are a small family of closely related enzymes, which are essential to mammalian physiology. This class of metalloenzymes employs tetrahydrobiopterin (BH4) as a two-electron donating cofactor for the activation of O2. Members of this class include phenylalanine (PheH), tyrosine (TyrH) and tryptophan (TrpH) hydroxylases, which effect regiospecific aromatic hydroxylations of the namesake amino acids. 

The NADPH-cytochrome P-450 system, commonly known as the mixed-function oxygenase (MFO) system, is the most important enzyme system involved in the Phase I oxidation reactions. Cytochrome P-450 system, localized in the smooth endoplasmic reticulum of cells of most mammalian tissues, is particularly abundant in the liver. This system contains a number of isozymes which are versatile in that they catalyze many types of reactions including aliphatic and aromatic hydroxylations and epoxidations,... 

Oxidations are probably the most common reactions in drug metabolism. They are catalyzed by enzymes classified as mixed oxygenases because they req uire both a reducing agent (TPNH) and atmospheric oxygen. These enzymic reactions include aromatic hydroxylation, side-chain oxidation, N-dealkylatlon, O-dealkylatlon, sulfoxide formation, and deamination. 

Hydroxylation may also take place at nitrogen atoms, resulting in hydroxyl-amines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by mono-oxygenases to epoxides, highly reactive electrophiles that are hepato-toxic and possibly carcinogenic. 

Institute of Health) shift.80,110,111 Originally, the term NIH shift was used as a phenomenological description of the consequence of hydroxylation of aromatic compounds by mixed-function oxygenases. These enzymes catalyze the oxidation of aromatic substrates by deriving oxygen from molecular oxygen and not from water.80,110,111 Later studies narrowed the term to include arene oxide involvement.80... 

The oxidative cyclization of an ortho-hydroxy-methoxy-substituted aromatic system giving a methylenedioxy group is also known to involve a cytochrome P-450-dependent mono-oxygenase. This enzyme hydroxylates the methyl to yield a formaldehyde hemiacetal intermediate, which can cyclize to the methylenedioxy bridge (the acetal of formaldehyde) by an ionic mechanism (Figure 2.21). 

N-oxidation can occur in a number of ways to give either hydroxylamines from primary and secondary amines [Eqs. (11) and (12)], hydroxamic acids from amides, or N-oxides from tertiary amines [Eq. (13)]. The enzyme systems involved are either cytochrome P450 or a flavoprotein oxygenase. Hydroxylamines may be further oxidized to a nitro compound via a nitroso intermediate [Eq. (11)]. Oximes can be formed by rearrangement of the nitroso intermediate or N-hydroxylation of an imine, that could in turn be derived by dehydration of a hydroxylamine [Eq. (11)]. N-Oxides may be formed from both tertiary arylamines and alkylamines and from nitrogen in heterocyclic aromatic systems, such as a pyridine ring. 

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