Proteins adrenal protein

Mitotane, or o,p -DDD, is an oral medication used in the treatment of adrenocortical carcinoma. Chemically it is an isomere of DDT. Following its metabolism in the adrenal cortex to a reactive acyl chloride intermediate, mitotane covalently binds to adrenal proteins, specitically inhibiting adrenal cortical hormone production. The drug accumulates in fat tissue. It is eliminated mainly by the kidneys with a half-life of 18-159 days. Common side effects include anorexia, nausea, lethargy, sleepiness and skin problems. 

The resolution of two high spin forms in adrenal mitochondria has been exploited in studies of the stimulation of steroid biosynthesis by ACTH and the effects of stress. Mitochondria from stressed rats showed increased amounts of high spin P-450, most notably in that corresponding to cholesterol side chain cleavage and similar but not identical effects were observed when hypophysectomised rats were treated with ACTH [118]. This supports the thesis that ACTH stimulation increases the availability of cholesterol for side chain cleavage. In adrenals, ESR can also be used to monitor the presence of reducing equivalents to P-450 as, in this case, the P-450 is linked to NADPH via an iron-sulphur protein, adrenal ferredoxin. This shows typical signals on reduction at g = 2.01, 1.94 [119]. A similar iron-sulphur protein (g = 2.03, 1.94) occurs in mammalian testes connected with a P-450 system [120]. 

Daaka Y, Luttrell LM, Lefkowitz RJ. Switching of the coupling of the P2-adren-ergic receptor to different G proteins by protein kinase A. Nature 1997 390 8 8-91. 

Wilson (1967) has reported on the use of low temperatures (— 196 C) to sharpen the absorption bands of some nonheme iron proteins, e.g., ferredoxins of spinach and of Clostridium acidi-urici, and an adrenal protein. All three of these nonheme proteins have absorption maxima near 700 nm which disappear on reduction by dithionite. The oxidized spinach ferredoxin has two additional absorptions, a shoulder near 830 nm and a weak maximum at 930 nm. Wilson (1967) investigated the possibility that the absorbance of these bands, particularly the 714 nm band of spinach ferre-doxin, is sensitive to protein conformational changes in a manner analogous to the 695 nm band of ferricytochrome c (Schejter and George, 1964). 

The adrenal cortex produces steroidal hormones that are associated with carbohydrate, fat, and protein metabolism, electrolyte balance, and gonadal functions (58). One of these, cortisone [53-06-5] ( ) demonstrated a remarkable ability to relieve the symptoms of inflammatory conditions... 

Adrenaline (epinephrine) is a catecholamine, which is released as a neurotransmitter from neurons in the central nervous system and as a hormone from chromaffin cells of the adrenal gland. Adrenaline is required for increased metabolic and cardiovascular demand during stress. Its cellular actions are mediated via plasma membrane bound G-protein-coupled receptors. 

In mitochondria (Fig. lb), the electron acceptor protein is also a flavoprotein termed NADPH-adrenodoxin reductase (MW 50 kDa) because it was discovered in the adrenal cortex and because it donates its electrons not directly to the P450 but to the smaller redox protein adrenodoxin (MW 12.5 kDa). The two iron-sulphur clusters of this protein serve as electron shuttle between the flavoprotein and the mitochondrial P450. 

Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP) is a 38-amino acid peptide (PACAP-38), which is widely expressed in the central nervous system. PACAP is most abundant in the hypothalamus. It is also found in the gastrointestinal tract, the adrenal gland and in testis. Its central nervous system functions are ill-defined. In the periphery, PACAP has been shown to stimulate catecholamine secretion from the adrenal medulla and to regulate secretion from the pancreas. Three G-protein coupled receptors have been shown to respond to PACAP, PAQ (PACAP type I) specifically binds PACAP, VPACi and VPAC2 also bind vasoactive intestinal peptide (VDP). Activation of PACAP receptors results in a Gs-mediated activation of adenylyl cyclase. 

Blake, M.J., Udelsman, R., Feulner, G.J., Norton, D.D., Holbrook, N.J. (1991). Stress induced heat shock protein 70 expression in adrenal cortex An ACTH-sensitive. age-dependent response. Proc. Natl. Acad. Sci. USA 88, 9873-9877,... 

Figure 11-6. Cytochrome P450 hydroxylase cycle in microsomes. The system shown is typical of steroid hydroxylases of the adrenal cortex. Liver microsomal cytochrome P450 hydroxylase does not require the iron-sulfur protein FejSj. Carbon monoxide (CO) inhibits the indicated step.

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450cl7) that catalyzes 17tt-hydroxylation. This is therefore a dual function protein. The lyase activity is important in both the adrenals and... 

Testiculat androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH. 

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