Steroid Dehydrogenase

Trichloroethylene 1.9 OS-phosphate buffer pH 7 (2/1) 20 /S-Hydroxy steroid dehydrogenase... 

The stereospecificity of hydrogen transfer for estradiol-17 and estradiol-17(3 dehydrogenases has been examined by George et a/.84>. These enzymes are both present in chicken liver, and have substrates which differ only in the chirality of their substituents at C—17. Both of these enzymes were shown to use the 4-pro-S or 4B proton of the NADPH. Since the steroid is a bulky substrate, the authors argue that the steric fit between pyridine nucleotide and steroid cannot be as important as the role played by the enzyme in directing the fit. This paper contains an interesting summary of other recent work on the stereospecificity of pyridine nucleotide dependent-steroid dehydrogenases. 

In patients suspected of congenital adrenal hyperplasia, to identify 21-hydroxylase deficiency, 11- hydroxylase deficiency, and 3l3-hydroxy-A5 steroid dehydrogenase deficiency, based on the steroids that accumulate in response to ACTH administration (see Figure 39-1 and Chapter 39)... 

There is considerable interest in understanding the structural bases for these differences because this information would be very useful in designing steroids and other compounds to selectively regulate the activity of one or more steroid dehydrogenases as a means of treating hormone-responsive diseases. There is precedent for this kind of treatment in the use of licorice extract from the root of the plant Glycyrrhiza glabra [15,27] to treat Addison s disease,... 

Figure 6d shows the modeled a helix F interface in pig 17 P-hydroxy steroid dehydrogenase type 4. Leucine-169 is 2.9 A from glycine-173. Leucine-174 is 4.3 A from alanine-162 and 3.3 A from alanine-166. There also is a hydrogen bond between serine-165 and serine-175, which are 3 A apart. 

N. Prospects for the Application of Structure-Function Analysis of Steroid Dehydrogenases in Hormone Therapy... 

In the last two years there has been impressive progress in understanding the structure of steroid dehydrogenases that are important in regulating blood pres... 

Considering the explosive pace of biomedical research and the new developments in computers for sophisticated structural analyses, the next few years promise to yield important advances in design of new hormone therapies based on the knowledge of the structure of steroid dehydrogenases. 

Enzyme defect Mevalonate kinase 3/ -Hydroxy-steroid dehydrogenase 3/M Iydroxy-sterol 8- 7-isomerase 3/I-Hydroxysterol 14-reductase 3/1-1 Iydroxysterol A5-dcsaturasc 3/ -Hydroxysterol 24-reductase 3/l-Hydroxysterol 7-reductase... 

ACTH stimulation may distinguish three forms of "late-onset" (nonclassic) congenital adrenal hyperplasia from states of ovarian hyperandrogenism, all of which may be associated with hirsutism. In patients with deficiency of 21-hydroxylase, ACTH stimulation results in an incremental rise in plasma 17-hydroxyprogesterone, the substrate for the deficient enzyme. Patients with 11-hydroxylase deficiency manifest a rise in 11-deoxycortisol, while those with 3B-hydroxy-5 5 steroid dehydrogenase deficiency show an increase of 17-hydroxypregnenolone in response to ACTH stimulation. 

Some of the effects of glucocorticoids can be attributed to their binding to aldosterone receptors (AR). Indeed, ARs bind aldosterone and cortisol with similar affinity. A mineralocorticoid effect of cortisol is avoided in some tissues by expression of 11 B-hydroxy steroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal affinity for aldosterone receptors. 

Trilostane is a 3 B-17 hydroxy steroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones and is comparable to aminoglutethimide. Its side effects are predominantly gastrointestinal adverse effects occur in about 50% of patients with both agents. There is no cross-resistance or crossover of side effects between these compounds. 

M (decreased testicular protein, 3 beta-hydroxy steroid dehydrogenase and serum testosterone)... 

Fig. 6. Biosynthetic pathways for corticosteroids. (TT) indicates position of hydroxylation HSD, hydroxy-steroid dehydrogenase.

Bachem, C.W.B., Horvath, B., Trindale, L., Claassens, M., Davelaar, E., Jordi, W., and Visser, R.G.F., A potato tuber expressed mRNA with homology to steroid dehydrogenases affects gibberellin levels and plant development, Plant J., 25, 595-604, 2001. 

A chemically similar approach to kcat inhibition has been used by Strickler and others (93). These workers have used 17/3-[(lS)-l-hy-droxy-2-propnyl]androst-4-en-3-one, Compound XVIII, as an inactivator of the S. hydrogenans 3a,20ft steroid dehydrogenase. This derivative is a substrate of the enzyme, and is converted by it to Compound XIX, the actual reactive species, which presumably inactivates by an addition reaction across the triple bond. 

A single 3/8-hydroxy-steroid dehydrogenase A5-3-oxo-steroid isomerase complex is present in human adrenal301 but a similar complex isolated from rat mitochondria was thought to be a redistribution artefact.302 The dimeric form of the A5-3-oxo-steroid isomerase from Pseudomonas species has a molecular weight of 26 800 dalton and is unusually stable to dissociation on dilution 303 it may be the catalytically active species. The enzyme from a bacterial source is irreversibly inhibited by an acetylenic analogue of the natural substrate.304... 

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