Steroid Hydroxysteroid dehydrogenase

Testosterone, the principal male sex steroid hormone, is synthesized in five steps from cholesterol, as shown below. In the last step, five isozymes catalyze the 17/3-hydroxysteroid dehydrogenase reactions that interconvert 4-androstenedione and testosterone. Defects in the synthesis or action of testosterone can impair the development of the male phenotype during embryogenesis and cause the disorders of human sexuality termed male pseudohermaphroditism. Specifically, mutations in isozyme 3 of the 17/3-hydroxysteroid dehydrogenase in the fetal testis impair the for-... 

An impressive indication of the high regioselectivity of hydroxysteroid dehydrogenases (HSHDs) was reported for the oxidation of various hydroxyl groups at the steroid core ofbile acids [26] (Scheme 9.1). The hydroxy-substituents at positions 3, 7, and 12 could be selectively addressed depending on the hydroxysteroid... 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

Burton, PJ. and Waddell, B.J., Dual function of 1 lP-hydroxysteroid dehydrogenase in placenta Modulating placental glucocorticoid passage and local steroid action, Biol. Reprod., 60, 234, 1999. 

Like all steroids, aldosterone enters the target cell and combines with cytosolic mineralocorticoid receptor. Such receptors are not entirely specific for aldosterone and will also bind cortisol, the principal glucocorticoid hormone. The receptors are protected from cortisol activation by 11 3 hydroxysteroid dehydrogenase which... 

Hilhorst, R., Spruijt, R., Laane, C., and Veeger, C. (1984). Rules for the regulation of enzyme-activity in reversed micelles as illustrated by the conversion of apolar steroids by 20-beta-hydroxysteroid dehydrogenase. Eur. J. Biochem., 144, 459-66. 

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.

Peltoketo H, Nokelainen P, Palo YS, Vihko R, Vihko P (1999) Two 17P-hydroxysteroid dehydrogenases (17HSDs) of estriadol biosynthesis 17HSD type 1 and type 7. J Steroid Biochem Mol Biol, 69(1-6) 431-439. 

Reactions catalyzed by 11 (3-hydroxysteroid and 17(3-hydroxysteroid dehydrogenases, (a) 11 (3-hydroxysteroid dehydrogenase type 1, an NADPH-dependent enzyme, catalyzes the conversion of the inactive steroid, cortisone, to cortisol, which is the biologically active glucocorticoid. 11 (3-hydroxysteroid dehydrogenase type 2, an NAD+-dependent enzyme, catalyzes the reverse direction, (b) 17(3-hydroxysteroid dehy-drogenase type 1, an NADPH-dependent enzyme, catalyzes the reduction of estrone to estradiol. Type 2, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone. Type 3, an NADPH-dependent enzyme, catalyzes the reduction of androstene dione to testosterone. Type 4, an NAD+-dependent enzyme, catalyzes the oxidation of estradiol to estrone, and androstenediol to dehydroepiandrosterone. 

Baker ME. Licorice and enzymes other than 11 P-hydroxysteroid dehydrogenase. Steroids 59 1994 136-141. 

Table 5.3.5 Steroid excretions (/,ig/24 h) and diagnostic ratios in patients with 3fi-hydroxysteroid dehydrogenase type II (3(iHSD II) deficiency... 

Simonian MH. ACTH and thyroid hormone regulation of 3 beta-hydroxysteroid dehydrogenase activity in human fetal adrenocortical cells. J Steroid Biochem 1986 25(6) 1001-6. 

Brooks, J.D. and Thompson, L.U. 2005. Mammalian lignans and genistein decrease the activities of aromatase and 17p-hydroxysteroid dehydrogenase in MCF-7 cells. J. Steroid Biochem. Mol. Biol. 94, 461—467. 

This interconversion is catalaysed by 17)3-hydroxysteroid dehydrogenase (17/3-HSD), an enzyme generally found in the ER of numerous tissues such as adrenal, liver, testis, ovary and kidney. Like many of the enzymes described above, there appear to be different forms [52,87]. For example, rat adrenal cytosol and ER contain separate 17/3-HSDs, with NADH as the preferred cofactor. The rat testicular enzyme, however, prefers NADPH. Guinea-pig liver also contains two 17j3-HSDs, one solubilized from cytosol, the other associated with the ER [88], These enzymes exhibit different activities towards C19 steroids, the cytosolic one preferring 5/3-reduced 17-oxosteroids and the microsomal counterpart being involved with 5a-reduced steroids, such as 5a-DHT. In this case, the product of the reaction would be 5a-an-drostane-3,17-dione. 

See p. 224 in Biochemistry (2nd ed.) for role of 11-p-hydroxysteroid dehydrogenase in steroid synthesis. 

Fig. 10. Hypothesis for the interaction of the A-kinase (A-K) system activated by ACTH with the C-kinase system (C-K) in the long-term regulation of the enzymes of steroidogenesis throughout the adrenal cortex. The primary determinant of zonation of A-kinase and C-kinase activities, via zonation of cell surface receptors or other mechanisms, is hypothesized to be a gradient (e.g., of steroids) created by the pattern of blood flow in the adrenal cortex. The resultant levels of induction of steroidogenic enzymes are indicated by to show particular elevation and by to show particular lack of induction or suppression of induction. Other enzymes involved in steroidogenesis are shown in parentheses. SCC=cholesterol side-chain cleavage enzyme 3/3=3/3-hydroxysteroid dehydrogenase 17a=17a-hy-droxylase 21 =21-hydroxylase 11/3= 11/3-hydroxylase CMO= corticosterone methyl oxidase activity of 11/3-hydroxylase. Secreted steroids are indicated as B=corticosterone Aldo=aldosterone F=cortisol DHEA(S)= dehydroepiandrosterone (sulfate).

In the fields of allergy and respiration, examples include 2-oxo-3-aminoazepine derivatives which act as dual neurokinin (tachykinin) NK1/NK2 receptor probes for development of options for treatment of asthsma and other airway diseases <07BMCL890> and benzo[l, 5]diazepine derivatives as new non-steroidal inhibitors of 17-P-hydroxysteroid dehydrogenase, an enzyme associated with hormone-dependent and neuronal diseases <07JEIMC29>. 

The saxl (hypersensitive to abscisic acid and auxin) mutant probably has a defect in the oxidation and isomerization of 3p-hydroxy-A precursors to 3-oxo-A steroids (Ephritikhine et ah, 1999). AtHSDl (At5g50600) encodes a protein with homology to animal ll- 3-hydroxysteroid dehydrogenase (Li et ah, 2007) however, no obvious sequence similarities exist with the 3P-HSD involved in cardenolide bios)mthesis (see Section 6.3.1.2). 

Benach, J., Filling, G., Oppermann, U.C.T., Roversi, P, Bricogne, G., Bemdt, K., Jornvall, H. and Ladenstein, R. (2002) Structure of bacterial 3p/17fJ-hydroxysteroid dehydrogenase at 1.2 A resolution a model for multiple steroid recognition. Biochemistry, 41,14659-68. 

Finsterbusch, A., Lindemann, R, Grimm, R., Eckerskom, C. and Luckner, M. (1999) A(5)-3p-hydroxysteroid dehydrogenase from Digitalis lanata Ehrh. - a multifunctional enzyme in steroid metabolism Planta, 209,478-86. 

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