Enzyme steroidogenic

Another important but infrequent modification of peptides is a-N-acetylation (Figs 18-5,18-7). During POMC processing, a-N-acetylation greatly increases the skin-darkening potency of ACTH(1-13)NH2 while abolishing both the adrenal steroidogenic potency of ACTH and the opiate activity of (3-endorphin [2]. The enzyme(s) responsible for this modification has not yet been purified or cloned. 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

Compagnone NA, Bulfone A, Rubenstein JL, Mellon SH. 1995. Steroidogenic enzyme P450c 17 is expressed in the embryonic central nervous system. Endocrinology 136 5212-5223. 

Mellon SH, Deschepper CF. 1993. Neurosteroid biosynthesis genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 629 283-292. 

Pezzi V, Mathis JM, Rainey WE, Carr BR. 2003. Profiling transcript levels for steroidogenic enzymes in fetal tissues. J Steroid Biochem Mol Biol 87 181-189. 

Yu L, Romero DG, Gomez-Sanchez CE, Gomez-Sanchez EP. 2002. Steroidogenic enzyme gene expression in the human brain. Mol Cell Endocrinol 190 9-17. 

Chronic Addison s disease congenital adrenal hyperplasia (genetic disorder due to deficiency of steroidogenic enzymes). 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

Slow-binding (i.e., slow on rate) inhibition (e.g., inhibition of the steroidogenic enzyme CYP19A1 by 19-azido-androstenedione)... 

Once cholesterol is transferred to the inner mitochondrial membrane of steroidogenic tissues such as adrenals, ovaries and testes, it encounters the enzyme system known as the cholesterol SCC system. This probably comprises 20- and 22-hydroxylases and a C-20,22-lyase, all tightly bound to the inner face of the membrane and associated with a specific cytochrome />-450scc. In addition, molecular 02 is necessary together with NADPH reductase and non-haem iron sulphur protein, which are called adrenodoxin reductase and adrenodoxin, respectively, in the adrenal [24] (Fig. 3). 

The structure and properties of this enzyme have been reviewed thoroughly by Talalay and his co-workers (42). Isomerase activities have been observed in all mammalian steroidogenic tissues. However, these mammalian isomerases have been difficult to study due to their mem-... 

In addition to the stimulatory actions of LH and hCG on steroidogenesis in Leydig cells and ovarian cells, these hormones also cause a refractoriness or desensitization of that same steroidogenic response. This may involve a loss of LH receptors (down regulation), an uncoupling of the LH receptor from the adenylate cyclase, an increase in the metabolism of cyclic AMP due to an increased phosphodiesterase activity and a decrease in the activities in some of the enzymes in the pathways of steroidogenesis (see Ref. 69 for other references). 

Fig. 3. Steroidogenic pathway in granulosa cells. A. Lipoprotein in receptors. B. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase). C. Acyl-coenzyme A (cholesterol acyl transferase). D. Cholesterol esterase. E. Cholesterol transport to the mitochondria. F. Cholesterol side-chain cleavage enzymes (phospholipid membrane environment and enzyme levels). G. 3/3-Hydroxysteroid dehydrogenase (3/3-HSD). H. 20a-Hydroxysteroid dehydrogenase (20a-HSD). I. Aromatases.

The rate of total steroidogenesis is determined by the rate of supply of cholesterol to cytochrome P-450scc. The rate of flux through this step determines the rate of synthesis of the sum of the steroid products, but does not determine the rate of synthesis of any individual steroid. The pattern of steroidogenesis, i.e. which steroids are produced and in what ratio, is determined by the relative activities of the enzymes of the steroidogenic pathway beyond the formation of pregnenolone. 

Fig. 7. Hypothesis for the action of ACTH in increasing the level of steroidogenic enzymes, in this case 17a-hydroxylase. In this model, cyclic AMP activates cyclic AMP-dependent protein kinase which by a series of unknown steps results in the accumulation of mRNA coding for a regulatory protein (17a-RP). After translation of this mRNA, the 17a-RP is hypothesized to translocate to the nucleus, where it activates the transcription of the cytochrome /M50,7 gene. This is one of several hypotheses which account for the sensitivity of cytochrome P-450 gene expression to inhibition of protein synthesis. From Ref. 27.

The cyclic AMP-dependent protein kinase system is involved in the effects of ACTH in both the short term (stimulation of conversion of cholesterol to pregnenolone) and in the long term (increased synthesis of steroidogenic enzymes). In the interaction of the ACTH/cyclic AMP system with other intracellular messengers,... 

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