Steroid biosynthetic enzymes

PED was recently shown to inhibit an additional steroid biosynthetic enzyme, namely steroid 19-hydroxylase (aromatase) from bovine adrenals. The observation that steroid 19-hydroxylase is the rate-limiting enzyme in the metabolic formation of 19-nordeoxy-corticosterone, a natural mineralo-corticosteroid that has been implicated in some forms of human and experimental hypertension may bear some implications for the treatment... 

Fig. 3. Gonadal steroid biosynthetic pathway and the catalytic enzymes 1) cytochrome P-450scc 2) -hydroxysteroid dehydrogenase 3) 17a-hydroxylase (P-450scc17) 4) 17,20-desmolase or 17,20-lyase 5) 17(3-hydroxysteroid dehydrogenase 6) 5a-reductase and 7) P-450 aromatase.

Rationally, 5/3-reduclase deficiency would not be a cause of MPH, but it seems appropriate to place this disorder adjacent to its 5a-counterpart. 5/3-Reductase (AKR1D1) is an essential bile-acid biosynthetic enzyme and patients with disabling mutations in this enzyme have a clinical phenotype associated with cholestasis and fiver failure. In addition to its importance in bile-acid synthesis, this aldoketo-reductase is responsible for reducing approximately two-thirds of the mass of synthesized androgens, corticosteroids, and aldosterone prior to their excretion, so has a vital role in steroid metabolism. 

The excessive production of thyroid hormone in Graves disease is associated with an enlarged thyroid gland, but in this case a circulating immunoglobulin that mimics the activity of thyroid stimulating hormone (TSH) is implicated. Finally, we saw in an earlier section how an inappropriate steroid hormone may be secreted in excessive amounts when specific enzymes in the adrenal steroid biosynthetic pathway are present at inadequate levels. 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

Attempts to use the secosteroid biosynthetic enzymes in a chemoenzymatic synthesis have recently proved successful. An acetone powder from P. americana transformed gorgosterol to 9(11)-secogorgosterol in a quantitative yield on a 5 mg scale [82]. The transformation was found to require both NAD and NADP. Interestingly, this chemoenzymatic process proved to be applicable to the production of a variety of known and novel 9( 11 )-secosterols indicating the lack of specificity of the enzymes involved and the utility as a synthetic tool [83], The secosteroids 48 - 51 were produced from their corresponding steroid in yields of 30 - 78%. 

Henry HL (2001) The 25(OH)D3/la,25(OH)2D3 24i -hydroxylase a catabolic or biosynthetic enzyme Steroids 66 391-398 Kasuga H, Hosogane N, Matsuoka K, Mori 1, Sakura Y, Shimakawa K, Shinki T, Suda T, Ta-ketomi S (2002) Characterization of transgenic rats constitutively expressing vitamin D-24-hy-droxylase gene. Bioehem Biophys Res Commun 297 1332-1338... 

Numerous effects of nicotine, sometimes also including those of its congeners, on mammalian enzymes have been reported, e.g. competitive inhibition of certain enzymes of the glucocorticoid and sex steroid biosynthetic pathways, e.g., the... 

Molybdate is also known as an inhibitor of the important enzyme ATP sulfurylase where ATP is adenosine triphosphate, which activates sulfate for participation in biosynthetic pathways (56). The tetrahedral molybdate dianion, MoO , substitutes for the tetrahedral sulfate dianion, SO , and leads to futile cycling of the enzyme and total inhibition of sulfate activation. Molybdate is also a co-effector in the receptor for steroids (qv) in mammalian systems, a biochemical finding that may also have physiological implications (57). 

For an organism to eliminate a lipophilic, chemically inert xenobiotic, it is usually hrst necessary to oxidize it to a more polar form. In addition, many biosynthetic pathways that produce steroid hormones, prostaglandins, leukotrienes, etc. involve oxidative steps. Organisms have evolved many enzymes to carry out these oxidations. Oxidation can occur by addition of oxygen (without addition of hydrogen which would represent hydration), removal of hydrogen atoms (without removal of oxygen which would represent dehydration), or simply removal of electrons. 

Stereospecific 2,3-epoxidation of squalene, followed by a nonconcerted carbocationic cyclization and a series of carbocationic rearrangements, forms lanosterol [79-65-0] (77) in the first steps dedicated solely toward steroid synthesis (109,110). Several biomimetic, cationic cydizations to form steroids or steroidlike nuclei have been observed in the laboratory (111), and the total synthesis of lanosterol has been accomplished by a carbocation—olefin cydization route (112). Through a complex series of enzyme-catalyzed reactions, lanosterol is converted to cholesterol (2). Cholesterol is the principal starting material for steroid hormone biosynthesis in animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to be normal constituents, in trace amounts, in tissues that are actively synthesizing cholesterol. 

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