Co

Fe2+-C0 tw

Flavoprotein (oxidized form)

Flavoprotein (reduced form)

Steroid

Steroid—OH

Steroid

Steroid—OH

FIGURE 2-27 Electron transport chains for sterol hydroxylases. (A) Mitochondrial hydroxylases showing the participation of the three protein components, ferredoxin oxidoreductase, ferredoxin, and a P450 hydroxylase. (B) Endoplasmic reticulum hydroxylases showing the participation of the two protein components, P450 reductase and a P450 hydroxylase.

calization of the various hydroxylase enzymes with the sequence of steroid movement through a metabolic pathway indicates the important role of cellular com-partmentalization. Thus, in the conversion of cholesterol into Cortisol in the adrenal cortex, the steroid must move sequentially from the mitochondria (side chain cleavage) to the microsomes (17a- and 21-hydroxylation) and then back to the mitochondria (11/3-hydroxylation).

Depending upon whether the cytochrome P450 hydroxylase is localized in the mitochondria or microsomes, there are two slightly different electron transport chains that function to transfer a pair of electrons from NADPH to the cytochrome P450 enzyme. These are presented in Figure 2-27. In the mitochondrial system there are at least three separate components: (i) a flavoprotein dehydrogenase known as ferredoxin oxidoreductase, which accepts the electrons from NADPH; (ii) a nonheme iron protein, termed ferredoxin5 (molecular weight 13,000), which accepts the

5 In the older literature, this nonheme iron protein was discovered in the adrenals and termed adrenodoxin. With the appreciation of the generic functioning of this heme protein in mitochondrial P450 hydroxylation in many tissues it is now referred to as ferredoxin.

electrons from the flavoprotein and transfers them to (iii) the cytochrome P450 hydroxylase protein. The microsomal system lacks a ferredoxin component; thus, the flavoprotein dehydrogenase transfers electrons directly to the cytochrome P450 enzyme.

The most important component of the electron transport chain is the cytochrome P450 protein, in that it determines the substrate specificity and dictates the precise site of hydroxylation. Each P450 hydroxylase has a substrate-binding domain that is comparable to the ligand-binding domains of receptors and plasma transport proteins for steroid hormones (see Section VI.B). Basically, the three-dimensional structure of the substrate-binding domain of a P450 hydroxylase determines which substrates are able to acquire a new hydroxy 1 group.

Figure 2-28 presents a scheme describing the complex series of steps associated with electron transfer and hydroxylation of steroids.

2. Ferredoxin

Ferredoxin, which has «116 amino acids (12 kDa), is synthesized as a larger preproprotein having both carboxy-terminal (—60 amino acids) and amino-

Substrate (SH)

Substrate (SH)

cyt P-450(Fe3+*022>SH

Cure Tennis Elbow Without Surgery

Cure Tennis Elbow Without Surgery

Everything you wanted to know about. How To Cure Tennis Elbow. Are you an athlete who suffers from tennis elbow? Contrary to popular opinion, most people who suffer from tennis elbow do not even play tennis. They get this condition, which is a torn tendon in the elbow, from the strain of using the same motions with the arm, repeatedly. If you have tennis elbow, you understand how the pain can disrupt your day.

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