Cortisone Reductase Research Articles

11β-hydroxystéroïde déshydrogénases. Avancées récentes

11β-hydroxysteroide dehydrogenase (11β-OHSD) enzymes exhibit a regulating action upon cortisol metabolism before access to its receptors. Two types of isoenzymes have been described, type 2 being the most anciently known. Type 2 11β-OHSD, which changes cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney, that protects mineralocorticoid receptors from illicit activation by glucocorticoids. Mutations of the gene coding for this enzyme has been demonstrated in apparent mineralocorticoid excess, which induces hypertension and hypokalemia with low renin and aldosterone levels. Polymorphisms of this gene could modulate essential hypertension and also be responsible for certain forms of acquired apparent mineralocorticoid excess especially after liquorice intoxication, in hypothyroidism, Cushing syndrome, and chronic renal insufficiency. Type 1 11β-OHSD, which changes cortisone into cortisol, is a reductase, mainly located in liver and adipose tissue. Functional defects of this enzyme have been shown in polycystic ovaries and cortisone reductase deficiency. By contrast, metabolic syndrome, corticoid-induced osteoporosis, and glaucoma are linked to a local over-activity of this enzyme. The understanding of action mechanisms of these two enzymes currently leads to 11β-OHSD inhibitors development, therefore opening new therapeutic strategies, especially in metabolic syndrome.

Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome

There are close phenotypic similarities between cortisone reductase deficiency (CRD), a rare abnormality of cortisone metabolism, and polycystic ovary syndrome (PCOS). As there is evidence that CRD results from digenic mutations involving the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) and hexose-6-phosphate dehydrogenase (H6PD), we sought to establish whether CRD-associated variants in these genes, individually or in combination, influence susceptibility to PCOS. Case-control, family-based association and quantitative-trait analyses. A UK case sample comprising 256 nuclear families ascertained from a PCOS offspring and 213 singleton PCOS cases plus 549 control subjects. All subjects were genotyped for CRD-related variants in HSD11B1 (rs12086634) and H6PD (rs6688832). Testosterone was measured with an in-house radioimmunoassay using ether extraction and dextran-coated charcoal separation. Case-control analyses revealed no differences in genotype distribution between PCOS and controls for rs12086634 or rs6688832 (both P = 0.84). Three per cent of cases and 2.4% of controls had genotype combinations (three or more variant alleles at the two sites) considered characteristic of CRD (P = 0.73). There were no departures from expectation in the family-based association studies, and no significant associations between genotypes (individually or in combination) and BMI, WHR or testosterone. The variants in HSD11B1 and H6PD typed, though implicated in causation of CRD, do not influence susceptibility to PCOS. It seems likely that additional variants within these genes are required for the development of CRD.

Genetic Variation in 11β-Hydroxysteroid Dehydrogenase Type 1 Predicts Adrenal Hyperandrogenism among Lean Women with Polycystic Ovary Syndrome

Elevated adrenal androgen levels are common in polycystic ovary syndrome (PCOS), but the underlying pathogenetic mechanism is poorly understood. In the rare cortisone reductase deficiency, impaired regeneration of active cortisol from inert cortisone by 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) results in compensatory activation of ACTH secretion and adrenal hyperandrogenism. 11beta-HSD1 deficiency may protect against obesity and its metabolic consequences because of impaired regeneration of cortisol in adipose tissue. Our objective was to investigate a functional polymorphism in HSD11B1 (T-->G in the third intron rs12086634, which associates with lower 11beta-HSD1 activity) in PCOS with and without obesity. We conducted a case-control study in lean and obese PCOS patients and controls at an academic hospital. Participants included 102 Caucasian PCOS patients and 98 controls comparable for age, weight, and race. We assessed genotype distribution and influence of genotypes on clinical, hormonal, and metabolic parameters. The G allele was significantly related to PCOS status (P = 0.041), and this association was mainly attributable to lean (P = 0.025), rather than obese (P = 0.424), PCOS patients. The G allele was associated with lower 0800-0830 h plasma cortisol (P < 0.001) and higher cortisol response to ACTH(1-24) (P < 0.001) in all women with PCOS and with higher dehydroepiandrosterone sulfate levels (P < 0.001), greater suppression of dehydroepiandrosterone sulfate by dexamethasone (P < 0.001), and lower fasting plasma low-density lipoprotein cholesterol (P = 0.002) levels in lean PCOS women. Genetic variation in 11beta-HSD1 contributes to enhanced cortisol clearance and compensatory adrenal hyperandrogenism in lean patients with PCOS but may be protective against obesity and some features of the metabolic syndrome.

Uncoupled Redox Systems in the Lumen of the Endoplasmic Reticulum: PYRIDINE NUCLEOTIDES STAY REDUCED IN AN OXIDATIVE ENVIRONMENT

The redox state of the intraluminal pyridine nucleotide pool was investigated in rat liver microsomal vesicles. The vesicles showed cortisone reductase activity in the absence of added reductants, which was dependent on the integrity of the membrane. The intraluminal pyridine nucleotide pool could be oxidized by the addition of cortisone or metyrapone but not of glutathione. On the other hand, intraluminal pyridine nucleotides were slightly reduced by cortisol or glucose 6-phosphate, although glutathione was completely ineffective. Redox state of microsomal protein thiols/disulfides was not altered either by manipulations affecting the redox state of pyridine nucleotides or by the addition of NAD(P)+ or NAD(P)H. The uncoupling of the thiol/disulfide and NAD(P)+/NAD(P)H redox couples was not because of their subcompartmentation, because enzymes responsible for the intraluminal oxidoreduction of pyridine nucleotides were distributed equally in smooth and rough microsomal subfractions. Instead, the phenomenon can be explained by the negligible representation of glutathione reductase in the endoplasmic reticulum lumen. The results demonstrated the separate existence of two redox systems in the endoplasmic reticulum lumen, which explains the contemporary functioning of oxidative folding and of powerful reductive reactions.

Genotypes at 11β-Hydroxysteroid Dehydrogenase Type 11B1 and Hexose-6-Phosphate Dehydrogenase Loci Are Not Risk Factors for Apparent Cortisone Reductase Deficiency in a Large Population-Based Sample

Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the hexose-6-phosphate dehydrogenase (H6PD) gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry three of a possible four minor alleles at the two loci. The objective of this study was to confirm the postulated digenic inheritance mechanism for ACRD. This was a population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD. The study comprised 3551 individuals in a population-based sample (50% black, 35% white, and 15% Hispanic). The main outcome measure was association between genotypes and risk for polycystic ovarian syndrome. Both polymorphisms occurred more frequently than previously reported. Thus, ACRD genotypes (at least three of four minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying zero, three, or four minor alleles. Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or 'kidney' isozyme and an inherited form of hypertension, 'apparent mineralocorticoid excess'. 'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.Conversely, 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11beta-HSD1 'knockout'--'cortisone reductase deficiency'--has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11beta-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert active cortisol and inactive cortisone. 11 beta-HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11 beta-HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11 beta-HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11 beta-HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11 beta-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11 beta-HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11 beta-HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11 beta-HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11 beta-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11 beta-HSD1 oxo-reductase activity whilst simultaneously increasing 11 beta-HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11 beta-HSD1 oxo-reductase activity, independent of 11 beta-HSD1 mRNA levels. H6PDH expression increased 5.3-fold across adipocyte differentiation (P < 0.05) and was associated with a switch from 11 beta-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11 beta-HSD1 oxo-reductase activity in intact cells. Through its interaction with 11 beta-HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.

The Crystal Structure of Guinea Pig 11β-Hydroxysteroid Dehydrogenase Type 1 Provides a Model for Enzyme-Lipid Bilayer Interactions

The metabolic reduction of 11-keto groups in glucocorticoid steroids such as cortisone leads to the nuclear receptor ligand cortisol. This conversion is an example of pre-receptor regulation and constitutes a novel pharmacological target for the treatment of metabolic disorders such as insulin resistance and possibly other derangements observed in the metabolic syndrome, such as hyperlipidemia, hypertension, and lowered insulin secretion. This reaction is carried out by the NADPH-dependent type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1), an enzyme attached through an integral N-terminal transmembrane helix to the lipid bilayer and located with its active site within the lumen of the endoplasmic reticulum. Here we report the crystal structure of recombinant guinea pig 11beta-HSD1. This variant was determined in complex with NADP at 2.5 A resolution and crystallized in the presence of detergent and guanidinium hydrochloride. The overall structure of guinea pig 11beta-HSD1 shows a clear relationship to other members of the superfamily of short-chain dehydrogenases/reductases but harbors a unique C-terminal helical segment that fulfills three essential functions and accordingly is involved in subunit interactions, contributes to active site architecture, and is necessary for lipid-membrane interactions. The structure provides a model for enzyme-lipid bilayer interactions and suggests a funneling of lipophilic substrates such as steroid hormones from the hydrophobic membrane environment to the enzyme active site.

11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

Cooperativity between 11β-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-phosphate Dehydrogenase in the Lumen of the Endoplasmic Reticulum

The functional coupling of 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase was investigated in rat liver microsomal vesicles. The activity of both enzymes was latent in intact vesicles, indicating the intraluminal localization of their active sites. Glucose-6-phosphate, a substrate for hexose-6-phosphate dehydrogenase, stimulated the cortisone reductase activity of 11beta-hydroxysteroid dehydrogenase type 1. Inhibition of glucose-6-phosphate uptake by S3483, a specific inhibitor of the microsomal glucose-6-phosphate transporter, decreased this effect. Similarly, cortisone increased the intravesicular accumulation of radioactivity upon the addition of radiolabeled glucose-6-phosphate, indicating the stimulation of hexose-6-phosphate dehydrogenase activity. A correlation was shown between glucose-6-phosphate-dependent cortisone reduction and cortisone-dependent glucose-6-phosphate oxidation. The results demonstrate a close cooperation of the enzymes based on co-localization and the mutual generation of cofactors for each other.

Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency.

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase.

Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.

Apparent Cortisone Reductase Deficiency: A Functional Defect in 11 -Hydroxysteroid Dehydrogenase Type 1

Apparent Cortisone Reductase Deficiency: A Functional Defect in 11 -Hydroxysteroid Dehydrogenase Type 1

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now decreased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blots of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme.

The 20α‐hydroxysteroid dehydrogenase of Streptomyces hydrogenans

In addition to the well-known 3 alpha,20 beta-hydroxysteroid dehydrogenase ('cortisone reductase'), Streptomyces hydrogenans produces a relatively stable, NAD-dependent 20 alpha-hydroxysteroid dehydrogenase of molecular mass approximately 48 kDa. This enzyme catalyzes the transfer of hydrogen from the 4-pro-S position of NADH.

Study of 3 alpha, 20 beta-hydroxysteroid dehydrogenase with an enzyme-generated affinity alkylator: dual enzyme activity at a single active site.

The substrate 17 beta-[(1S)-1-hydroxy-2-propynyl]-androst-4-en-3-one (beta-HPA) and its enzyme-generated alkylating product 17 beta-(1-oxo-2-propynyl)androst-4-en-3-one (OPA) were synthesized to investigate the relationship between the 3 alpha and 20 beta activities observed in commercially available cortisone reductase (EC 1.1.1.53) from Streptomyces hydrogenans. beta-HPA, a substrate [apparent Km = 145 microM; Vmax = 63 nmol (min microgram)-1], when enzymatically oxidized by cortisone reductase of OPA, inactivates simultaneously the 3 alpha and 20 beta activities in a time-dependent and irreversible manner following pseudo-first-order kinetics. OPA alone, an affinity alkylating steroid (KI = 40.5 microM; k3 = 1.8 X 10(-2) S-1), simultaneously inactivates 3 alpha and 20 beta activities in a time-dependent and irreversible manner. At pH 7, the t 1/2 of enzyme inactivation for beta-HPA (10 h) or OPA (41 min) is slower than at pH 9.2 (beta-HPA, 16 min, and OPA, 3.3 min). Substrates (progesterone, 20 beta-hydroxypregn-4-en-3-one, and 5 alpha-dihydrotestosterone), but not all steroids (20 al]ha-delta 4-pregn-4-en-3-one and 17 beta-estradiol), protect against loss of both enzyme activities by beta-HPA and OPA. The alpha isomer of HPA is not enzymatically oxidized and therefore does not cause inactivation of either 3 alpha or 20 alpha activity. Thus, beta-HPA functions as a substrate for the enzymatic generation of a powerful affinity alkylator of cortisone reductase. Second, the identical change in both the 3 alpha and 20 beta activities in all experimental conditions clearly results from dual enzyme activity at a single enzyme active site.

‘Affinity’ chromatography of steroid-transforming enzymes with a non-steroidal ligand

The chromatographic behaviour of an avian oestradiol-17 beta dehydrogenase, the 3(17) beta-hydroxy steroid dehydrogenase from Pseudomonas testosteroni and cortisone reductase from Streptomyces dehydrogenans was studied on columns of p-(phenoxypropoxy)aniline attached to CNBr-activated Sepharose. The ligand was effective in adsorbing the oestradiol dehydrogenase from a partially purified extract of chicken liver, and the cortisone reductase was perferentially retained when mixtures of the three dehydrogenases were applied to columns in 10mM-buffer. Under these conditions the 3(17)beta-hydroxy steroid dehydrogenase was eluted in the front, but was adsorbed in the presence of 3 M-KCl. beta-N-Acetylglucosaminidase present in the liver preparation was not retained by the ligand, whereas lactate dehydrogenase from rabbit muscle was adsorbed in a manner similar to the retention pattern found on affinity chromatography with 2',5'-ADP--Sepharose. The mean overall purification of the oestradiol dehydrogenase was 13-fold, with a mean recovery of 53%. p-(Phenoxypropoxy)aniline offers promise for the purification of steroid-transforming enzymes where elution with substrate or cofactor is not wanted. It is also suggested that the ligand may be of service in the purification of receptors of hormonal steroids.

Cortisone reductase and some small non-steroid analogues of its steroid substrates [proceedings

Conference Article| June 01 1977 Cortisone Reductase and Some Small Non-Steroid Analogues of its Steroid Substrates IAN H. WHITE; IAN H. WHITE *Department of Chemical Pathology, University of Aberdeen, Aberdeen AB9 2ZD, Scotland, U.K. Search for other works by this author on: This Site PubMed Google Scholar JONATHAN JEFFERY JONATHAN JEFFERY †Department of Biochemistry, University of Aberdeen, Aberdeen AB9 1AS, Scotland, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1977) 5 (3): 723–724. https://doi.org/10.1042/bst0050723 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation IAN H. WHITE, JONATHAN JEFFERY; Cortisone Reductase and Some Small Non-Steroid Analogues of its Steroid Substrates. Biochem Soc Trans 1 June 1977; 5 (3): 723–724. doi: https://doi.org/10.1042/bst0050723 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1977 Biochemical Society1977 Article PDF first page preview Close Modal You do not currently have access to this content.

The altered specificity of cortisone reductase with certain retroandrostan-3-one substrates

The retro steroids 17beta-hydroxy-5beta,9beta,10alpha-androstan-3-one and 5beta,9beta,10alpha-androstane-3,17-dione were good substrates for cortisone reductase in the presence of NADH, and the products corresponded to the respective 3beta-hydroxy compounds, in which the 3beta-hydroxyl group is axial and the absolute configuration is 3S. The analogous natural steroids 17beta-hydroxy-5beta,9alpha,10beta-androstan-3-one and 5beta,9alpha,10beta-androstane-3,17-dione were very poor substrates, and gave the corresponding 3alpha(equatorial,3R)-hydroxy compounds, and, in the latter case, also an appreciable amount of 3beta(axial, 3S)-hydroxy-5beta,9alpha,10beta-androstan-17-one. The natural steroids 17beta-hydroxy-5alpha,9alpha,10beta-androstan-3-one and 5alpha,9alpha,10beta-androstane-3,17-dione were better substrates than the retro steroid 17beta-hydroxy-5alpha,9beta,10alpha-androstan-3-one, but were not such good substrates as the retro steroids 17beta-hydroxy-5beta,9beta,10alpha-androstan-3-one and 5beta,9beta,10alpha-androstane-3,17-dione. Unlike these retro steroid 5beta,9beta,10alpha-androstan-3-ones, the natural steroids 17beta-hydroxy-5alpha,9alpha,10beta-androstan-3-one and 5alpha,9alpha,10beta-androstane-3,17-dione gave the corresponding 3alpha(axial,3R)-hydroxy compounds. The retro steroid 17beta-hydroxy-5alpha,9beta,10alpha-androstan-3-one was not a good substrate, and the product of reaction corresponded to the 3alpha(axial,3R)-hydroxy compound. The nature of substrate recognition by this enzyme is discussed in the light of these structure-activity relationships.

Influence of the Structure of the D Ring of various 20-Oxo Steroids on their Behaviour as Substrates for Cortisone Reductase

Conference Article| October 01 1974 Influence of the Structure of the D Ring of various 20-Oxo Steroids on their Behaviour as Substrates for Cortisone Reductase IAN H. WHITE; IAN H. WHITE * Search for other works by this author on: This Site PubMed Google Scholar JONATHAN JEFFERY JONATHAN JEFFERY 1Department of Biochemistry, University of Aberdeen, Marischal College, Aberdeen AB9 1AS, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1974) 2 (5): 984. https://doi.org/10.1042/bst0020984 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation IAN H. WHITE, JONATHAN JEFFERY; Influence of the Structure of the D Ring of various 20-Oxo Steroids on their Behaviour as Substrates for Cortisone Reductase. Biochem Soc Trans 1 October 1974; 2 (5): 984. doi: https://doi.org/10.1042/bst0020984 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1974 Biochemical Society1974 Article PDF first page preview Close Modal You do not currently have access to this content.