Hydroperoxidases Use Hydrogen Peroxide Or An Organic Peroxide As Substrate

Two type of enzymes found both in animals and plants fall into this category: peroxidases and catalase.

Hydroperoxidases protect the body against harmful peroxides. Accumulation of peroxides can lead to generation of free radicals, which in turn can disrupt membranes and perhaps cause cancer and atherosclerosis. (See Chapters 14 and 45.)

Carrier (Ox)

Carrier-H2 (Red)

Carrier (Ox)

DEHYDROGENASE SPECIFIC FOR A

DEHYDROGENASE SPECIFIC FOR B

Figure 11-3. Oxidation of a metabolite catalyzed by coupled dehydrogenases.

Peroxidases Reduce Peroxides Using Various Electron Acceptors

Peroxidases are found in milk and in leukocytes, platelets, and other tissues involved in eicosanoid metabolism (Chapter 23). The prosthetic group is proto-heme. In the reaction catalyzed by peroxidase, hydrogen peroxide is reduced at the expense of several substances that will act as electron acceptors, such as ascorbate, quinones, and cytochrome c. The reaction catalyzed by peroxidase is complex, but the overall reaction is as follows:

PEROXIDASE

H2O2 + AH2

In erythrocytes and other tissues, the enzyme glutathione peroxidase, containing selenium as a prosthetic group, catalyzes the destruction of H2O2 and lipid hydroperoxides by reduced glutathione, protecting membrane lipids and hemoglobin against oxidation by peroxides (Chapter 20).

Catalase Uses Hydrogen Peroxide as Electron Donor & Electron Acceptor

Catalase is a hemoprotein containing four heme groups. In addition to possessing peroxidase activity, it is able to use one molecule of H2O2 as a substrate electron donor and another molecule of H2O2 as an oxidant or electron acceptor.

CATALASE

2H2O2

Under most conditions in vivo, the peroxidase activity of catalase seems to be favored. Catalase is found in blood, bone marrow, mucous membranes, kidney, and liver. Its function is assumed to be the destruction of hydrogen peroxide formed by the action of oxidases.

Figure 11-4. Mechanism of oxidation and reduction of nicotinamide coenzymes. There is stereospecificity about position 4 of nicotinamide when it is reduced by a substrate AH2. One of the hydrogen atoms is removed from the substrate as a hydrogen nucleus with two electrons (hydride ion, H-) and is transferred to the 4 position, where it may be attached in either the A or the B position according to the specificity determined by the particular dehydrogenase catalyzing the reaction. The remaining hydrogen of the hydrogen pair removed from the substrate remains free as a hydrogen ion.

CONH

CONH

CONH,

A Form

CONH,

B Form

CONH,

A Form

CONH,

B Form

Peroxisomes are found in many tissues, including liver. They are rich in oxidases and in catalase, Thus, the enzymes that produce H2O2 are grouped with the enzyme that destroys it. However, mitochondrial and microso-mal electron transport systems as well as xanthine oxidase must be considered as additional sources of H2O2.

OXYGENASES CATALYZE THE DIRECT TRANSFER & INCORPORATION OF OXYGEN INTO A SUBSTRATE MOLECULE

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, as follows.

Dioxygenases Incorporate Both Atoms of Molecular Oxygen Into the Substrate

The basic reaction is shown below:

Examples include the liver enzymes, homogentisate dioxygenase (oxidase) and 3-hydroxyanthranilate dioxygenase (oxidase), that contain iron; and L-trypto-phan dioxygenase (tryptophan pyrrolase) (Chapter 30), that 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.

Cytochromes P450 Are Monooxygenases Important for the Detoxification of Many Drugs & for the Hydroxylation of Steroids

Cytochromes P450 are an important superfamily of heme-containing monooxgenases, and more than 1000 such enzymes are known. Both NADH and NADPH donate reducing equivalents for the reduction of these cytochromes (Figure 11-5), which in turn are oxidized by substrates in a series of enzymatic reactions collectively known as the hydroxylase cycle (Figure 11-6). In liver microsomes, cytochromes P450 are found together with cytochrome b5 and have an important role in detoxification. 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 formation of mi-crosomal enzymes and of cytochromes P450.

Mitochondrial cytochrome P450 systems are found in steroidogenic tissues such as adrenal cortex, testis, ovary, and placenta and are concerned with the biosyn-

NADH-Flavoprotein2-Cyt b5 | > Stearyl-CoA desaturase

Amine oxidase, etc -Flavoprotein3

NADPH-*- Flavoprotein,-Cyt P450-Hydroxylation

^-Lipid peroxidation

Heme oxygenase

Figure 11-5. Electron transport chain in microsomes. Cyanide (CN-) inhibits the indicated step.

thesis of steroid hormones from cholesterol (hydroxylation at C22 and C20 in side-chain cleavage and at the 11P and 18 positions). In addition, renal systems catalyzing 1a- and 24-hydroxylations of 25-hydroxychole-calciferol in vitamin D metabolism—and cholesterol 7a-hydroxylase and sterol 27-hydroxylase involved in bile acid biosynthesis in the liver (Chapter 26)—are P450 enzymes.

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