The hyperandrogenism of polycystic ovary syndrome (PCOS) appears to be due to dysregulation of steroidogenesis within the ovaries and adrenal glands. P450c<em>17</em> is the key enzyme that regulates androgen synthesis. It is the only enzyme known to have the capacity to convert C21-precursors to the androgen pre-hormones, the <em>17</em>-<em>ketosteroids</em>. It is a single enzyme with two activities, <em>17</em>-hydroxylase and <em>17</em>,20-lyase. Thus, its regulation is a significant factor in the expression of hyperandrogenism. Androgen secretion is LH-dependent in the ovary and ACTH-dependent in the adrenal glands. The androgenic response to each of these tropic hormones seems to be modulated by intra-ovarian or intra-adrenal autocrine and paracrine mechanisms. This modulation serves to regulate steroid hormone secretion in tissue-specific ways. Insulin, IGFs and inhibin are among the many growth factors capable of augmenting the response to LH and ACTH. The insulin/IGF system stimulates P450c<em>17</em> mRNA expression and activities in the ovaries and adrenal glands. An integrating link between insulin resistance and hyperandrogenemia may be serine phosphorylation, which inhibits activity of the insulin receptor and promotes the <em>17</em>,20-lyase activity of P450c<em>17</em>. However, it must be kept in mind that there is some evidence for the existence of P450c<em>17</em>-independent pathways of androgen biosynthesis.

Ovarian steroid metabolism was investigated (i) during development in a normal inbred strain in which post-natal follicle growth has been described and (ii) in adult hypogonadal (hpg) mice which lack GnRH and have very low serum concentrations of gonadotrophins. Tissue was incubated with [3H]pregnenolone or [3H]androstenedione and metabolites separated by t.l.c. or h.p.l.c. Progesterone was the major metabolite formed at all ages while androstenedione was the major androgen. Between 7 and 21 days there was an overall increase in steroidogenic enzyme activity with a peak of 5 alpha-reductase between 21 and 29 days. The major metabolite of progesterone around puberty was 5 alpha-pregnane-3 alpha-ol-20-one. A sharp increase in 20 alpha-hydroxysteroid dehydrogenase was observed after 38 days due, presumably, to the appearance of corpora lutea. Unlike the rat, androstanediol levels were low at all ages. Oestradiol was the major oestrogen formed from androstenedione with a peak of production at 38 days. In the adult hpg mouse metabolism was similar to that of the 7-day normal mouse although <em>17</em>-<em>ketosteroid</em> reductase and aromatase levels were very low compared to normal animals of any age, indicating that gonadotrophin stimulation is involved in the expression of activity by these enzymes.

3alpha-Hydroxysteroid dehydrogenases (3alpha-HSDs) inactivate steroid hormones in the liver, regulate 5alpha-dihydrotestosterone (5alpha-DHT) levels in the prostate, and form the neurosteroid, allopregnanolone in the CNS. Four human 3alpha-HSD isoforms exist and correspond to AKR1C1-AKR1C4 of the aldo-keto reductase (AKR) superfamily. Unlike the related rat 3alpha-HSD (AKR1C9) which is positional and stereospecific, the human enzymes display varying ratios of 3-, <em>17</em>-, and 20-<em>ketosteroid</em> reductase activity as well as 3alpha-, <em>17</em>beta-, and 20alpha-hydroxysteroid oxidase activity. Their k(cat) values are 50-100-fold lower than that observed for AKR1C9. Based on their product profiles and discrete tissue localization, the human enzymes may regulate the levels of active androgens, estrogens, and progestins in target tissues. The X-ray crystal structures of AKR1C9 and AKR1C2 (human type 3 3alpha-HSD, bile acid binding protein and peripheral 3alpha-HSD) reveal that the AKR1C2 structure can bind steroids backwards (D-ring in the A-ring position) and upside down (beta-face inverted) relative to the position of a 3-<em>ketosteroid</em> in AKR1C9 and this may account for its functional plasticity. Stopped-flow studies on both enzymes indicate that the conformational changes associated with binding cofactor (the first ligand) are slow; they are similar in both enzymes but are not rate-determining. Instead the low k(cat) seen in AKR1C2 (50-fold less than AKR1C9) may be due to substrate "wobble" at the plastic active site.

<em>17</em>Beta-hydroxysteroid dehydrogenase activity represents a group of several isoenzymes (<em>17</em>HSDs) that catalyze the interconversion between highly active <em>17</em>beta-hydroxy- and low activity <em>17</em>-<em>ketosteroids</em> and thereby regulate the biological activity of sex steroids. The present study was carried out to characterize the expression of <em>17</em>HSD isoenzymes in human mammary epithelial cells and breast tissue. In normal breast tissues <em>17</em>HSD types 1 and 2 mRNAs were both evenly expressed in glandular epithelium. In two human mammary epithelial cell lines, mRNAs for <em>17</em>HSD types 1, 2 and 4 were detected. In enzyme activity measurements only oxidative <em>17</em>HSD activity, corresponding to either type 2 or type 4 enzyme, was present. The role of <em>17</em>HSD type 4 in estrogen metabolism was further investigated, using several cell lines originating from various tissues. No correlation between the presence of <em>17</em>HSD type 4 mRNA and <em>17</em>HSD activity in different cultured cell lines was detected. Instead, oxidative <em>17</em>HSD activity appeared in cell lines where <em>17</em>HSD type 2 was expressed and reductive <em>17</em>HSD activity was present in cells expressing <em>17</em>HSD type 1. These data strongly suggest that in mammary epithelial cell lines the oxidative activity is due to type 2 <em>17</em>HSD and that oxidation of <em>17</em>beta-hydroxysteroids is not the primary activity of the <em>17</em>HSD type 4 enzyme.

Elevated concentrations of peptide hormones have been described previously in human breast fluid. In the current study, the levels of cortisol, progesterone, testosterone, dihydrotestosterone, androsterone, androsterone sulfate, dehydroisoandrosterone, dehydroisoandrosterone sulfate, estradiol, estrone, estradiol sulfate, and estrone sulfate were measured. The levels of the four <em>17</em>-<em>ketosteroids</em> and the two estrogen sulfates were markedly elevated over the plasma level, while that of the other compounds was the same or only slightly higher than the plasma levels of the same compounds.

The inducible 3-<em>ketosteroid</em>-delta 1-dehydrogenase of Nocardia corallina which catalyzes the introduction of a double bond into the position of carbon 1 and 2 of ring A of 3-<em>ketosteroid</em> has been obtained in four steps with a 50% yield and 360-fold purification. The enzyme is homogeneous as judged by SDS-gel electrophoresis and is a monomeric protein with a molecular weight of 60,500. The isoelectric point of the enzyme is about 3.1. The enzyme contains 1 mol of flavin adenine dinucleotide per mol of protein, and has a typical flavoprotein absorption spectrum with maxima of 458, 362 and 268 nm. The enzyme is very stable in the absence of added cofactors, and catalyzes the dehydrogenation of delta 4-3-<em>ketosteroids</em> in the presence of phenazine methosulfate, which acts as an excellent electron acceptor. Potassium ferricyanide and cytochrome c did not act as electron acceptors. The delta 1-dehydrogenation was also stimulated by molecular oxygen with stoichiometric production of hydrogen peroxide and delta 1,4-3-<em>ketosteroid</em>. The optimum pH is 10 for dehydrogenation using phenazine methosulfate, and is between 8.5 and 10 for the oxidase reaction. The enzyme oxidizes a wide variety of 3-<em>ketosteroids</em>, but not 3 beta-hydroxysteroids. 3-<em>Ketosteroids</em> having an 11 alpha- or 11 beta-hydroxyl group were oxidized at slow rates. The purified enzyme catalyzes efficiently aromatization of the A-ring of 19-nortestosterone and 19-norandrostenedione to produce estradiol and estrone. 19-Hydroxytestosterone, 19-hydroxyandrostenedion and 19-oxotestosterone were converted to the respective phenolic steroids with cleavage of the C10 side-chain. Activities of 3-<em>ketosteroid</em>-delta 4-dehydrogenase, delta 5-3-<em>ketosteroid</em>-4,5-isomerase, 3 beta-hydroxysteroid dehydrogenase and <em>17</em> beta-hydroxysteroid dehydrogenase were not observed in the purified preparations. Properties of this novel flavoprotein enzyme are discussed.

Hydroxysteroid (<em>17</em>beta) dehydrogenase 7 (HSD<em>17</em>B7) has been shown to catalyze the conversion of both estrone to estradiol (<em>17</em>-<em>ketosteroid</em> reductase activity) and zymosterone to zymosterol (3-<em>ketosteroid</em> reductase activity involved in cholesterol biosynthesis) in vitro. To define the metabolic role of the enzyme in vivo, we generated knockout mice deficient in the enzyme activity (HSD<em>17</em>B7KO). The data showed that the lack of HSD<em>17</em>B7 results in a blockage in the de novo cholesterol biosynthesis in mouse embryos in vivo, and HSD<em>17</em>BKO embryos die at embryonic day (E) 10.5. Analysis of neural structures revealed a defect in the development of hemispheres of the front brain with an increased apoptosis in the neuronal tissues. Morphological defects in the cardiovascular system were also observed from E9.5 onward. Mesodermal, endodermal, and hematopoietic cells were all detected by the histological analysis of the visceral yolk sac, whereas no organized vessels were observed in the knockout yolk sac. Immunohistological staining for platelet endothelial cell adhesion molecule-1 indicated that the complexity of the vasculature also was reduced in the HSD<em>17</em>B7KO embryos, particularly in the head capillary plexus and branchial arches. At E8.5-9.5, the heart development and the looping of the heart appeared to be normal in the HSD<em>17</em>B7KO embryos. However, at E10.5 the heart was dilated, and the thickness of the cardiac muscle and pericardium in the HSD<em>17</em>B7KO embryos was markedly reduced, and immunohistochemical staining for GATA-4 revealed that HSD<em>17</em>B7KO embryos had a reduced number of myocardial cells. The septum of the atrium was also defected in the knockout mice.

The <em>17</em>beta-hydroxysteroid dehydrogenases (<em>17</em>beta-HSDs) play an important role in the regulation of steroid hormones, such as estrogens and androgens, by catalysing the reduction of <em>17</em>-<em>ketosteroids</em> or the oxidation of <em>17</em>beta-hydroxysteroids using NAD(P)H or NAD(P)(+) as cofactor. The enzyme activities associated with the different <em>17</em>beta-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues, such as the testis, ovary, and placenta, but also in a large series of peripheral intracrine tissues. In the nineties, several new types of <em>17</em>beta-HSD were reported, indicating that a fine regulation is carried out. More importantly, each type of <em>17</em>beta-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution. These findings are important for understanding the mode of action of the <em>17</em>beta-HSD family. From a therapeutic point of view, this means that selectivity of drug action could be achieved by targeting a particular <em>17</em>beta-HSD isozyme. Consequently, each study that leads to better knowledge of the inhibition of <em>17</em>beta-HSDs deserves attention from scientists working in this and related fields. Being involved in the last step of the biosynthesis of sex steroids from cholesterol, the <em>17</em>beta-HSD family constitutes an interesting target for controlling the concentration of estrogens and androgens. Thus, inhibitors of <em>17</em>beta-HSDs are useful tools to elucidate the role of these enzymes in particular biological systems or for a therapeutic purpose, especially to block the formation of active hydroxysteroids that stimulate estrogeno-sensitive pathologies (breast, ovarian, and endometrium cancers) and androgeno-sensitive pathologies (prostate cancer, benign prostatic hyperplasia, acne, hirsutism, etc). Few review articles have however focussed on <em>17</em>beta-HSD inhibitors although this family of steroidogenic enzymes includes interesting therapeutic targets for the control of several diseases. Furthermore, inhibitors of <em>17</em>beta-HSDs constitute a growing field in biomedical research and there is a need for an exhaustive review on this topic. In addition to giving an up-to-date description of inhibitors of all <em>17</em>beta-HSD isoforms (types 1-8), the present review will also address, when possible, the isoform selectivity and residual estrogenic or androgenic activity often associated with steroidal inhibitors.

Ataxia-telangiectasia is a syndrome of progressive cerebellar ataxia and other neurological manifestations associated with conjunctival and cutaneous telangiectases and with recurrent sino-pulmonary infections. Immunological and endocrine abnormalities occur. Two girls with this disease are described. The first had only minor respiratory infections; her serum proteins and immunity responses appeared normal. The second had recurrent pulmonary infections and bronchiectasis; she also exhibited sclerodermatous changes, poor development of secondary sexual characteristics with low urinary excretion of <em>17</em>-<em>ketosteroids</em>, and lymphopenia. Autopsy at <em>17</em> years showed bilateral ovarian dysgerminomata and excessive cutaneous collagen as well as atrophy, and perhaps hypoplasia, of adrenals, thymus, spleen and lymphoid tissue (after steroid therapy). The cerebellum exhibited cortical degeneration. Both lungs were fibrotic with old and recent bronchopneumonia and bronchiectasis. The left lung was studied by injection of a latex preparation; no arteriovenous aneurysms were found, but the smaller pulmonary vessels showed some unusual morphological characteristics.

Biological rhythms play a prominent role in the human life cycle. The endogenous rhythms are entrained by the environment and have an astronomical counterpart which is obvious for daily, monthly, and yearly rhythms, and may possibly also be present in weekly rhythms. Circadian rhythms are present in, e.g. testosterone levels, spontaneous birth, strokes, and death from cardiovascular causes. Circaseptan rhythms are present in, e.g. spontaneous birth, <em>17</em>-<em>ketosteroid</em> levels, myocardial infarctions, and strokes. The relationship of these rhythms with the suprachiasmatic nucleus (SCN) has not yet been established. Circatrigintan rhythms, such as the menstrual cycle, have so far not been associated with the SCN. Circannual rhythms are present in, e.g. mood, suicides, reproduction, birth weight, sleep and season of birth of psychiatric patients. The human SCN shows strong circadian and circannual fluctuations in the number of neurons expressing vasopressin. The vasopressin and VIP cell population of the SCN develop late, i.e. for a major part postnatally. After the age of 50 the amplitudes of circadian and circannual fluctuations of the vasopressin cell numbers are reduced whereas the number of vasopressin expressing neurons decreases after the age of 80 and do so even more and earlier in Alzheimer's disease. Sex differences are present in the shape of the vasopressin subnucleus of the SCN and in the vasoactive intestinal polypeptide (VIP) cell number. The sex differences in the SCN, the doubling of the number of vasopressin neurons in the SCN of homosexual men, and a variety of animal experimental observations indicate that the SCN is involved in sexual behavior and reproduction. The exact role of the SCN in these processes is subject to current research.

<em>17</em>-<em>Ketosteroid</em> reductase (<em>17</em>KSR), also known as <em>17</em> beta-hydroxysteroid dehydrogenase, catalyzes the reversible interconversion of estradiol to estrone and of androstenedione to testosterone. Using a recently cloned human placental <em>17</em>KSR cDNA, we show that the 1.4-kilobase mRNA for this enzyme is detected only in tissues producing estrogens, and a 2.4-kilobase mRNA is detected in some estrogenic tissues and some androgenic tissues. This tissue distribution suggests that the interconversion of androstenedione and testosterone may be mediated by a different enzyme. Southern blotting studies show that the mRNA for this estrogenic <em>17</em>KSR is encoded by two very similar genes localized to chromosome <em>17</em>cen----q25 by analysis of DNA from mouse/human somatic hybrid cell lines. 8-Br-cAMP increases the abundance of estrogenic <em>17</em>KSR mRNA as well as mRNAs for other steroidogenic enzymes in JEG-3 choriocarcinoma cells. By contrast, cAMP decreases estrogenic <em>17</em>KSR mRNA in primary cultures of human cytotrophoblasts and human granulosa cells, a pattern of tropic regulation that differs from other steroidogenic enzyme mRNAs.

We describe a woman who developed adrenal insufficiency after removal of an apparently nonfunctional adrenal adenoma. She displayed no stigmata of Cushing's syndrome and had normal plasma and urinary cortisol levels. A second patient without clinical findings of Cushing's syndrome also had normal basal steroid levels. This patient displayed partial suppressibility with dexamethasone, had low-normal levels of serum corticotropin, and excreted a low concentration of urinary <em>17</em>-<em>ketosteroids</em>. She also developed mild adrenal insufficiency after the operation. We believe the adrenal adenomas in these patients secreted enough cortisol to suppress the contralateral adrenal gland but not enough hormone to elevate basal steroid levels. Therefore, we suggest that all patients with adrenal masses be studied with the overnight dexamethasone suppression test rather than basal steroid hormone measurements to detect low levels of autonomous cortisol secretion. In addition, patients with adrenal masses that are not removed surgically should have serial adrenal function tests performed.

AKR1C3 (also known as <em>17</em>beta-hydroxysteroid dehydrogenase type 5 or 3alpha-hydroxysteroid dehydrogenase type 2) functions as a 3-keto, <em>17</em>-keto and 20-<em>ketosteroid</em> reductase and as a 3alpha-, <em>17</em>beta- and 20alpha-hydroxysteroid oxidase. Relatively high mRNA expression of AKR1C3 was found in human prostate and mammary gland where it is implicated in regulating ligand access to the androgen and estrogen receptor, respectively. AKR1C3 is an interesting target for the development of agents for treating hormone-dependent forms of cancer like prostate cancer, breast cancer, and endometrial cancer. However, only a few clinically promising and selective inhibitors have been reported so far. Very potent inhibitors of AKR1C3 are the non-steroidal anti-inflammatory drugs, e.g. indomethacin or flufenamic acid. Also dietary phytoestrogens such as coumestrol, quercetin, and biochanin were reported to inhibit the enzyme in low micromolar concentrations. In this study, some dietary flavonoids and other phenolic compounds were tested for their ability to specifically inhibit AKR1C3. Carbonyl reduction of the anticancer drug oracin, which is a very good substrate for AKR1C3 and which could be well monitored by a sensitive HPLC system with fluorescence detection, was employed to determine the inhibitory potency of the compounds. Our results reveal that AKR1C3 could be potentially un-competitively inhibited by 2'-hydroxyflavanone, whose IC(50) value of 300nM is clinically promising. Moreover, since the inhibition is selective towards AKR1C3, 2'-hydroxyflavanone could be useful for treating or preventing hormone-dependent malignancies like prostate and breast cancer.

The <em>17</em>HSDs are a group of isozymes that catalyze the interconversion between high-activity <em>17</em> beta-hydroxysteroids and low-activity <em>17</em>-<em>ketosteroids</em>. In the present study, we characterized the expression of <em>17</em>HSD types 1 and 2 in normal and malignant gastrointestinal tissues and cells. Using the colon as a model for cancer of the gastrointestinal tract, expression of the <em>17</em>HSD enzymes in cancer development was studied and correlated with proliferation and differentiation markers as assessed by Ki67 and mucin staining, respectively. In normal colon and small intestine, <em>17</em>HSD type 2 mRNA was expressed in the surface epithelial cells and, to a lesser extent, in the cryptal epithelial cells. In colon-cancer specimens, <em>17</em>HSD type 2 expression was downregulated both in the tissues and in the cell lines and correlated inversely with the proliferation marker. No expression for the <em>17</em>HSD type 1 enzyme was observed in normal or cancerous gastrointestinal tract tissues. In line with the expression studies, <em>17</em>HSD activity measurements with colon cells showed that only the oxidative conversion of E2 to E1 was present, and Northern blot analysis showed the signal only for <em>17</em>HSD type 2. Localization of the ERs alpha and beta, assessed by immunohistochemistry and in situ hybridization, showed the presence of ER beta in the lamina propria of the colon. Our study shows that <em>17</em>HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. The decrease in expression of the type 2 enzyme may increase estrogen influence in colon cancer.

Cholesterol degradation is achieved through a complex metabolic pathway that starts with the oxidation of the <em>17</em>-alkyl side chain and the steroid ring system. In bacteria, the oxidation of the 3β-hydroxyl group and isomerization of the resulting cholest-5-en-3-one to cholest-4-en-3-one is catalyzed by hydroxysteroid dehydrogenase (HsdD) or cholesterol oxidase (ChoD). Genes encoding both enzymes were annotated in both fast and slow growing mycobacteria, however the enzymatic activity was confirmed for HsdD, exclusively. Here, we used homologous recombination to engineer multiple mutants, and directly show that both ChoD and HsdD are dispensable for cholesterol degradation in fast-growing Mycobacterium smegmatis mc(2)155 and slow-growing Mycobacterium tuberculosis H37Rv strains. The mutants deffective in the synthesis of ChoD, HsdD or both enzymes were able to grow in minimal media supplemented with cholesterol as a sole source of carbon and energy. Multiple mutants, defective in synthesis of ChoD, HsdD and <em>ketosteroid</em> dehydrogenase (KstD), showed attenuated growth in minimal medium supplemented with cholesterol and accumulated cholesterol degradation intermediates: androstendion (AD) and 9-hydroxy androstendion (9OHAD).

Steroid degradation genes of Comamonas testosteroni TA441 are encoded in at least two gene clusters: one containing the meta-cleavage enzyme gene tesB; and another consisting of ORF18, <em>17</em>, tesI, H, ORF11, 12, and tesDEFG. TesH and I are, respectively, the Delta(1)- and Delta(4)(5alpha)-dehydrogenase of the 3-<em>ketosteroid</em>, TesD is the hydrolase for the product of meta-cleavage reaction, and TesEFG degrade one of the product of TesD. In this report, we describe the identification of the function of ORF11 (tesA2) and 12 (tesA1). The TesA1- and TesA2-disrupted mutant accumulated two characteristic intermediate compounds, which were identified as 3-hydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,<em>17</em>-dione (3-HSA) and its hydroxylated derivative, 3,<em>17</em>-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,<em>17</em>-dione by MS and NMR analysis. A complementation experiment using a broad-host range plasmid showed that both TesA1 and A2 are necessary for hydroxylation of 3-HSA to 3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,<em>17</em>-dione (3,4-DHSA).

The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)isomerase (3beta-HSD) isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-<em>ketosteroids</em>, thus catalyzing an essential step in the formation of all classes of active steroid hormones. The 3beta-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. In humans, there are two 3beta-HSD isoenzymes, which were chronologically designated type I and II encoded by HSD3B1 and HSD3B2 gene, respectively. HSD3B1 gene encodes the almost exclusive 3beta-HSD isoenzyme expressed in the placenta and peripheral tissues, whereas HSD3B2 gene encodes the predominant 3beta-HSD isoenzyme expressed in the adrenal gland, ovary, and testis and its deficiency is responsible for a rare form of congenital adrenal hyperplasia causing various degrees of salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. Although an elevated ratio of Delta(5)-Delta(4)-steroids was considered to be the best biological parameter for the diagnosis of this autosomal recessive disorder, the most accurate criteria now appears to be the plasma levels of <em>17</em>-OH-pregnenolone greater than 100 nmol/L following ACTH stimulation. To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing, and 23 missense mutations) have been identified in the HSD3B2 gene in 56 individuals from 44 families suffering from classical 3beta-HSD deficiency. In almost all the cases, the functional characterization of HSD3B2 mutations has provided a molecular explanation for the heterogeneous clinical presentation of this disorder. Indeed these experiments confirm that no functional 3betaHSD type II isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form, whereas the non-salt-losing form results from specific missense mutation(s) in the HSD3B2 gene, which causes an incomplete loss of enzymatic activity thus leaving sufficient enzymatic activity to prevent salt wasting. Moreover, various mutations appear to have a drastic effect upon stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3beta-HSD deficiency. Thus, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily.