Oxygenases are concerned with the synthesis or degradation of many different types of metabolites. They catalyze the incorporation of oxygen into a substrate molecule in two steps: (1) oxygen is bound to the enzyme at the active site and (2) the bound oxygen is reduced or transferred to the substrate. Oxygenases may be divided into two subgroups, dioxygenases and monooxygenases.

Dioxygenases Incorporate Both Atoms of Molecular Oxygen Into the Substrate

 The basic reaction catalyzed by dioxygenases is as follows:

A + O₂ →AO₂

Examples include the liver enzymes, homogentisate dioxygenase (oxidase) and 3-hydroxyanthranilate dioxygenase (oxidase), which contain iron; and l-tryptophan dioxygenase (tryptophan pyrrolase) , which utilizes heme.

Monooxygenases (Mixed-Function Oxidases, Hydroxylases) Incorporate Only One Atom of Molecular Oxygen Into the Substrate

The other oxygen atom is reduced to water, an additional electron donor or cosubstrate (Z) being necessary for this purpose:

A — H + O₂ + ZH₂ → A — OH + H₂O + Z

Cytochromes P450 Are Monooxygenases Important in Steroid Metabolism & for the Detoxification of Many Drugs

Cytochromes P450 are an important superfamily of heme containing monooxygenases, and more than 50 such enzymes have been found in the human genome. They are located mainly in the endoplasmic reticulum in the liver and intestine, but are also found in the mitochondria in some tissues. The cytochromes participate in an electron transport chain in which both NADH and NADPH may donate reducing equivalents. Electrons are passed to cytochrome P450 in two types of reaction involving FAD or FMN. Class I systems consist of an FAD-containing reductase enzyme, an iron sulfur (Fe₂S₂ ) protein, and the P450 heme protein, while class II systems contain cytochrome P450 reductase, which passes electrons from FADH₂ to FMN (Figure 1). Class I and II systems are well characterized, but in recent years, other cytochromes P450, which do not fit into either category, have been identified. In the final step, oxygen accepts the electrons from cytochrome P450 and is reduced, with one atom being incorporated into H₂O and the other into the substrate, usually resulting in its hydroxylation. This series of enzymatic reactions, known as the hydroxylase cycle, is illustrated in Figure 2. In the endoplasmic reticulum of the liver, cytochromes P450 are found together with another heme-containing protein, cytochrome b₅ (see Figure 1) and together they have a major role in drug metabolism and detoxification. Cytochrome b5 also has an important role as a fatty acid desaturase. Together, cytochromes P450 and b₅ are responsible for about 75% of the modification and degradation of drugs which occurs in the body. The rate of detoxification of many medicinal drugs by cytochromes P450 determines the duration of their action. Benzpyrene, aminopyrine, aniline, morphine, and benzphetamine are hydroxylated, increasing their solubility and aiding their excretion. Many drugs such as phenobarbital have the ability to induce the synthesis of cytochromes P450.

Fig1. Cytochromes P450 and b₅ in the endoplasmic reticulum. Most cytochromes P450 are class I or class II. In addition to cytochrome P450, class I systems contain a small FAD-containing reductase and an iron sulfur protein, and class II contains cytochrome P450 reductase, which incorporates FAD and FMN. Cytochromes P450 catalyze many steroid hydroxylation reactions and drug detoxification steps. Cytochrome b₅ acts in conjunction with the FAD-containing cytochrome b₅ reductase in the fatty acyl-CoA desaturase (eg, stearoyl-CoA desaturase) reaction and also works together with cytochromes P450 in drug detoxification. It is able to accept electrons from cytochrome P450 reductase via cytochrome b₅ reductase and donate them to cytochrome P450.

Fig2. Cytochrome P450 hydroxylase cycle. The system shown is typical of steroid hydroxylases of the adrenal cortex. Liver microsomal cytochrome P450 hydroxylase does not require the iron-sulfur protein Fe₂S₂ . Carbon monoxide (CO) inhibits the indicated step.

Mitochondrial cytochrome P450 systems are found in steroidogenic tissues such as adrenal cortex, testis, ovary, and placenta and are concerned with the biosynthesis of steroid hormones from cholesterol (hydroxylation at C₂₂ and C₂₀ in side chain cleavage and at the 11β and 18 positions). In addition, renal systems catalyzing 1α- and 24-hydroxylations of 25-hydroxycholecalciferol in vitamin D metabolism—and cholesterol 7α-hydroxylase and sterol 27-hydroxylase involved in bile acid biosynthesis from cholesterol in the liver (see Chapters 26, 41)—are P450 enzymes.

مواضيع ذات صلة

Hydroperoxidases Use Hydrogen Peroxide or an Organic Peroxide as Substrate

اضطرابات استقلاب النوكليوتيدات البيريميدينية

اضطرابات استقلاب النكليوتيدات البورينية

تخليق النوكليوتيدات منقوصة الاكسجين ( dNTPs )

تقويض النوكليوتيدات البيريميدينية

Dehydrogenases Perform Two Main Functions

Oxidases Use Oxygen As A Hydrogen Acceptor

تخليق النكليوتيدات البيريميدينية

تقويض النوكليوتيدات البورينية

تنظيم استحداث البورينات

التخليق الحيوي للنوكليوتيدات البورينية

سبيل كيناز جانوس ومُنبِّغات الإشعار ومنشطات الانتساخ Jak/STATS Pathway