Aromatase enzyme complex

Estrogens are formed by the aromatization of androgens in a complex process that involves three hydroxyla-tion steps, each of which requires O2 and NADPH. The aromatase enzyme complex is thought to include a P450 monooxygenase. Estradiol is formed if the substrate of this enzyme complex is testosterone, whereas estrone results from the aromatization of androstenedione. 

Aminoglutethimide (Cytadren) is a competitive inhibitor of desmolase, the enzyme that catalyzes the conversion of cholesterol to pregnenolone it also inhibits 11-hydroxylase activity. This drug also reduces estrogen production by inhibiting the aromatase enzyme complex in peripheral (skin, muscle, fat) and steroid target tissues. 

In most mammals, estrogens (female sex steroid hormones) are synthesized from cholesterol using the parent ring structure, cyclopentanoperhydrophenan-threne of the estrane series. The steroidogenic pathway includes the production of the androgenic precursors dehydroepiandrosterone and androstenedione, the latter of which is converted to testosterone, then to estradiol-17/i. This requires aromatization of these andogenic precursors by an aromatase enzyme complex. The major source of estrogen in postmenopausal women is the conversion of androstenedione to estrone by aromatase activity... 

Anastrozole (Fig. 46.11) is a potent and highly selective, nonsteroidal aromatase inhibitor utilized in the treatment of advanced breast cancer that is hormone-responsive. It is considered to be second-line therapy (after tamoxifen) in the treatment of postmenopausal breast cancer. Anastrozole. a benzyltriazole derivative, competes with the natural substrate for binding to the active site of the aromatase. The mechanism of enzyme inhibition resides in the coordination of the triazole ring with the heme iron atom of the aromatase enzyme complex (161,162). This coordination ultimately prevents aromatization of androgens into estrogens and, therefore, deprives the tumor of estrogen. This effect is reversible. In the presence of anastrozole. estradiol levels are reduced to undetectable levels, with no adverse effects on levels of any other hormone, including cortisol and aldosterone. 

Aromatase catalyzes the conversion of C19 steroids (androgens) into Cig steroids (estrogens) containing a phenolic A ring (Scheme 3.1). It is an enzyme complex comprised of two proteins. One is nicotinamide adenine dinucleotide phosphate... 

The accepted pathway for the biosynthesis of the oestrogens from the appropriate androgen substrate is shown in Scheme 2.1. The conversion of either testosterone (16) or androstenedione (17) to their respective oestrogens, oestradiol and oestrone, is catalysed by a E-450-NADPH-flavoprotein-reduc-tase-dependent enzyme complex, aromatase (AR) [143, 144]. The overall... 

Note also that the estrogens (e.g., estradiol) are derived from the androgens by aromatization of a ring. This reaction is catalyzed by an enzyme complex called aromatase. Reactions catalyzed by aromatase represent the only known route for synthesis of aromatic rings in animal cells. 

Testosterone represents the immediate precursor of the oestrogens, the conversion being catalysed by the aromatase complex, i.e. a microsomal enzyme system. The biological actions of oestrogens may be summarized as ... 

Figure 19.8 A brief summary of the pathways for formation and secretion of oestradiol and progesterone within the cells of the follicle. Cholesterol is taken up by thecal cells in a complex with low density lipoprotein. In the thecal cells, cholesterol is converted to testosterone which is released to be taken up by granulosa cells where it is converted into oestradiol. For synthesis of progesterone in the granulosa cells, cholesterol is synthesised de novo within the cells from acetyl-CoA. In the follicle the enzyme aromatase, which produces the aromab c ring in the female sex hormones, is restricted to the granulosa cells. The reacrions that are stimulated by LH and FSH increase synthesis and, therefore, secretion of testosterone and increased synthesis of oestrogens and progesterone.

One approach to interfere with ER signalling is to reduce the circulating level of its ligand estradiol by inhibiting the enzyme aromatase. Aromatisation is the last step in the synthesis of estradiol. This reaction is catalysed by the P450 aromatase mono-oxygenase complex that is present in the smooth endoplasmic... 

In this case, a ferric porphyrin peroxo complex plays the role of the analogue of the reactive intermediate implicated in the third oxidative step of aromatase, the enzyme responsible for the conversion of androgens to estrogens (Scheme XI. 16). 

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