S-CoA FIGURE 21-13 Electron transfer in the desaturation of fatty acids in vertebrates.

Blue arrows show the path of electrons as two substrates—a fatty acyl-CoA and NADPH—undergo oxidation by molecular oxygen. These reactions take place on the lumenal face of the smooth ER. A similar pathway, but with different electron carriers, occurs in plants.

also sometimes called mixed-function oxidases or mixed-function oxygenases, to indicate that they oxidize two different substrates simultaneously. (Note here the use of "oxidase"—a deviation from the general meaning of this term noted above.)

There are different classes of monooxygenases, depending on the nature of the cosubstrate. Some use reduced flavin nucleotides (FMNH2 or FADH2), others use NADH or NADPH, and still others use a-ketoglutarate as the cosubstrate. The enzyme that hydroxylates the phenyl ring of phenylalanine to form tyrosine is a monooxygenase for which tetrahy-drobiopterin serves as cosubstrate (see Fig. 18-23). This is the enzyme that is defective in the human genetic disease phenylketonuria.

The most numerous and most complex monooxy-genation reactions are those employing a type of heme protein called cytochrome P-450. This cytochrome is usually present in the smooth ER rather than the mitochondria. Like mitochondrial cytochrome oxidase, cytochrome P-450 can react with O2 and bind carbon monoxide, but it can be differentiated from cy-tochrome oxidase because the carbon monoxide complex of its reduced form absorbs light strongly at 450 nm—thus the name P-450.

Cytochrome P-450 catalyzes hydroxylation reactions in which an organic substrate, RH, is hydroxy-lated to R—OH, incorporating one oxygen atom of O2; the other oxygen atom is reduced to H2O by reducing equivalents that are furnished by NADH or NADPH but are usually passed to cytochrome P-450 by an iron-sulfur protein. Figure 1 shows a simplified outline of the action of cytochrome P-450, which has intermediate steps not yet fully understood.

Cytochrome P-450 is actually a family of similar proteins; several hundred members of this protein family are known, each with a different substrate specificity. In the adrenal cortex, for example, a specific cytochrome P-450 participates in the hydroxyla-tion of steroids to yield the adrenocortical hormones (see Fig. 21-47). Cytochrome P-450 is also important in the hydroxylation of many different drugs, such as barbiturates and other xenobiotics (substances foreign to the organism), particularly if they are hy-drophobic and relatively insoluble. The environmental carcinogen benzo[a]pyrene (found in cigarette smoke) undergoes cytochrome P-450-dependent hydroxylation during detoxification. Hydroxylation of xenobiotics makes them more soluble in water and allows their excretion in the urine. Unfortunately, hydroxylation of some compounds converts them to toxic substances, subverting the detoxification system.

Reactions described in this chapter that are catalyzed by mixed-function oxidases are those involved in fatty acyl-CoA desaturation (Fig. 21-13), leukotri-ene synthesis (Fig. 21-16), plasmalogen synthesis (Fig. 21-30), conversion of squalene to cholesterol (Fig. 21-37), and steroid hormone synthesis (Fig. 21-47).

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